Hazardous agent injection system

ABSTRACT

A hazardous agent injection system including from about 0.02 ml to about 4.0 ml of methotrexate at a concentration of from about 7.5 mg/ml to about 150 mg/ml; a needle-assisted jet injector including a container configured to contain the methotrexate; a injection outlet member associated with the container; an injection-assisting needle coupled to the injection outlet member; a firing mechanism associated with the container; an energy source associated with the firing mechanism; and a trigger mechanism associated with the firing mechanism, wherein the needle-assisted jet injector is configured to eject the methotrexate from the injection outlet member such that the C max , T max  and bioavailability of the needle-assisted jet injected methotrexate falls between about 80% and about 125% of the C max , T max  and bioavailability of methotrexate delivered by a hand-powered syringe.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.13/257,555, filed 6 Mar. 2012, which in turn is a U.S. National StageEntry of the International Patent Application No. PCT/US2010/28011,filed 19 Mar. 2010, which in turn claims benefit of priority from U.S.Provisional Patent Application No. 61/162,114, filed 20 Mar. 2009, allof which are incorporated by reference herein by in their entirety.

FIELD

The disclosure relates to injection of hazardous agents.

BACKGROUND

Since the late 1980's hazardous agents, such as cytotoxic agents havebeen useful in managing and treating a number of diseases such asrheumatoid arthritis (and other autoimmune diseases), juvenilerheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus,steroid-resistant polymyositis or dermatomyositis, Wegener'sgranulomatosis, polyarteritis nodosa, and some forms of vasculitis.Hazardous agents tend to exhibit side effects, however, that are harmfulor toxic to the subject. Many of these side effects occur when hazardousagents are administered orally, but the oral form is generally thepreferred method of delivery of these agents due to its ease of use.

In addition to increased toxicity, variable and reduced bioavailabilityhas been observed for some hazardous agents, such as methotrexate, thatare orally administered. These limitations are particularly demonstratedwhen the oral dosing is escalated beyond 15 mg per week. It has beensuggested that with parenteral administration, such as by injection,more predictable, reproducible and complete bioavailability along withbetter therapeutic results could be achieved, particularly at higherdosages.

Only about 7% of the prescriptions for methotrexate written byrheumatologists are for an injectable formulation. Reasons forprescribing methotrexate injections are usually to improvebioavailability or to alleviate side effects. Physicians have expressedinterest in increasing the number of prescriptions for cytotoxic agentinjections, and particularly injections for home use and administrationby a patient. This is generally not considered feasible because it isnot possible to ensure that patients can reliably and repeatably draw anaccurate dose from vials and correctly administer the product bysubcutaneous (SC) injection, especially with agents used to treatpatients suffering from certain debilitating diseases. Additionally, thetoxicity of hazardous agents increases the risk that non-users of theinjections will come into contact with the cytotoxic agents in a homesetting. Insufficient data exists on the effect of low dose, chronicexposure to hazardous agents that are, or may be, candidates for homeuse or self-injection. In the absence of such information, practiceguidelines direct one to assume a high degree risk for injectablehazardous agents such as methotrexate, with the recommendation of formaldirectives and risk assessments, including formal training andmitigation strategies, to minimize risk (see Oliver, S., and Livermore,P., Administering subcutaneous methotrexate for inflammatory arthritis:RCN guidance for nurses, 2004; Royal College of Nursing, Wyeth,Publication Code 002 269). Specific directives include: preparation ofsyringes in dedicated pharmacies with aseptic preparation areas;administration performed in specific locations and only by adequatelytrained personnel; spillage kits located proximal to use areas;accounting for all who may be at risk in the event of an accident; andaudits to assess compliance and execution of risk mitigation strategies.Because of the need for such directives, and thus the large number ofprecautions that must be learned and followed in order to safely injecta hazardous agent, it is presently thought that it is not practical forhazardous agents, and particularly methotrexate, to be self-injected bya patient outside of a clinical setting or without the assistance of ahealth care provider.

SUMMARY

Thus, injector devices that allow for the safe self-administration ofhazardous agents are useful. In some embodiments, hazardous agents caninclude, without limitation, toxic agents, cytotoxic agents, highlypotent agents, agents that have profound physiological effects at lowdoses, analgesics, immunomodulating agents, IL-1 receptor antagonists,IL-2 alpha receptor antagonists, anti-rejection compounds, hormonalagents, prostaglandins, sedatives, anticholinergic agents, Parkinsonsdisease drugs, expensive agents, neuroleptic agents, tissue necrosisfactor (TNF) blockers, and other dangerous agents. Such injector deviceswould eliminate the risk of inadvertent contact of such agents to thesubject and would also protect to non-users from exposure or contactwith the hazardous agent(s). Examples of cytotoxic agents include,without limitation, 6-mercaptopurine, 6-thioinosinic acid, azathioprine,chlorambucil, cyclophosphamide, cytophosphane, cytarabine, fluorouracil,melphalan, methotrexate, uramustine, anti-cytokine biologicals, cellreceptor antagonists, cell receptor analogues, and derivatives thereof.Examples of highly potent agents include, without limitation, steroidssuch as dexamethasone, progesterone, somatostatin, and analoguesthereof; biologically active peptides such as teriparatide; andanticholinergics such as scopolamine. Examples of agents that haveprofound physiological effects at low doses include, without limitation,antihypertensives and/or blood pressure down regulators. Examples ofanalgesics include, without limitation, fentanyl, fentanyl citrate,morphine, meperidine, and other opioids. Examples of immunomodulatingagents include, without limitation, adalimumab (anti-tissue necrosisfactor monoclonal antibody or anti-TNF). Examples of IL-1 receptorantagonists include, without limitation, anakinra. Examples of IL-2alpha receptor antagonists include, without limitation, daclizumab andbasiliximab. Examples of anti-rejection compounds include, withoutlimitation, azathioprine, cyclosporine, and tacrolimus. Examples ofhormonal agents include, without limitation, testosterone, estrogen,growth hormone, insulin, thyroid hormone, follicle stimulating hormone(FSH), epinephrine/adrenaline, progesterone, parathyroid hormone,gonadotrophin releasing hormone (GHRH), leutinizing hormone releasinghormone (LHRH), other hormones such as those where contact with thehormone by members of the opposite sex can lead to side effects, andderivatives thereof. Examples of prostaglandins include, withoutlimitation, gamma-linolenic acid, docosahexanoic acid, arachidonic acidand eicosapentaenoic acid. Examples of sedatives include, withoutlimitation, barbiturates such as amobarbital, pentobarbital,secobarbital, and phenobarbitol; benzodiazepines such as clonazepam,diazepam, estazolam, flunitrazepam, lorazepam, midazolam, nitrazepam,oxazepam, triazolam, temazepam, chlordiazepoxide, and alprazolam; herbalsedatives such as ashwagandha, duboisia hopwoodii, prosantherastriatiflora, kava (piper methysticum), mandrake, valerian, andmarijuana; non-benzodiazepine sedatives (a.k.a. “Z-drugs”) such aseszopiclone, zaleplon, zolpidem, zopiclone; antihistamines such asdiphenhydramine, dimenhydrinate, doxylamine, and promethazine; and othersedatives such as chloral hydrate. Examples of anticholinergic agentsinclude, without limitation, dicyclomine, atropine, ipratropium bromide,oxitropium bromide, and tiotropium. Examples of Parkinson's diseasedrugs include, without limitation, levodopa, dopamine, carbidopa,benserazide, co-ceraldopa, co-beneldopa, tolcapone, entacapone,bromocriptine, pergolide, pramipexole, ropinirole, piribedil,cabergoline, apomorphine, and lisuride. Examples of expensive agentsinclude, without limitation, human growth hormone and erythropoietin.Examples of neuroleptic agents includes, without limitation,antipsychotics; butyrophenones such as haloperidol and droperidol;phenothiazines such as chlorpromazine, fluphenazine, perphenazine,prochlorperazine, thioridazine, trifluoperazine, mesoridazine,periciazine, promazine, triflupromazine, levomepromazine, promethazine,and pimozide; thioxanthenes such as chlorprothixene, clopenthixol,flupenthixol, thiothixene, and zuclopenthixol; atypical antipsychoticssuch as clozapine, olanzapine, risperidone, quetiapine, ziprasidone,amisulpride, asenapine, paliperidone, iloperidone, zotepine, andsertindole; and third generation antipsychotics such as aripiprazole andbifeprunox. Examples of TNF blockers includes, without limitation,etanercept.

In some embodiments, the hazardous agent can be selected from botulinumtoxin, injectable gold, 6-mercaptopurine, 6-thioinosinic acid,azathioprine, chlorambucil, cyclophosphamide, cytophosphane, cytarabine,fluorouracil, melphalan, methotrexate, uramustine, anti-cytokinebiologicals, cell receptor antagonists, cell receptor analogues,dexamethasone, progesterone, somatostatin, analogues of dexamethasone,analogues of progesterone, analogues of somatostatin, teriparatide,scopolamine, antihypertensives, blood pressure down regulators,fentanyl, fentanyl citrate, morphine, meperidine, other opioids,adalimumab (anti-tissue necrosis factor monoclonal antibody oranti-TNF), anakinra, daclizumab, basiliximab, azathioprine,cyclosporine, tacrolimus, testosterone, estrogen, growth hormone,insulin, thyroid hormone, follicle stimulating hormone (FSH),epinephrine/adrenaline, gamma-linolenic acid, docosahexanoic acid,arachidonic acid, eicosapentaenoic acid, amobarbital, pentobarbital,secobarbital, phenobarbitol, clonazepam, diazepam, estazolam,flunitrazepam, lorazepam, midazolam, nitrazepam, oxazepam, triazolam,temazepam, chlordiazepoxide, alprazolam, ashwagandha, duboisiahopwoodii, prosanthera striatiflora, kava (piper methysticum), mandrake,valerian, marijuana, eszopiclone, zaleplon, zolpidem, zopiclone,diphenhydramine, dimenhydrinate, doxylamine, promethazine, chloralhydrate, dicyclomine, atropine, ipratropium bromide, oxitropium bromide,tiotropium, levodopa, dopamine, carbidopa, benserazide, co-ceraldopa,co-beneldopa, tolcapone, entacapone, bromocriptine, pergolide,pramipexole, ropinirole, piribedil, cabergoline, apomorphine, lisuride,human growth hormone, erythropoietin, haloperidol, droperidol,chlorpromazine, fluphenazine, perphenazine, prochlorperazine,thioridazine, trifluoperazine, mesoridazine, periciazine, promazine,triflupromazine, levomepromazine, promethazine, pimozide,chlorprothixene, clopenthixol, flupenthixol, thiothixene,zuclopenthixol, clozapine, olanzapine, risperidone, quetiapine,ziprasidone, amisulpride, asenapine, paliperidone, iloperidone,zotepine, sertindole, aripiprazole, bifeprunox, etanercept, derivativesof any of the foregoing, and combinations of any of the foregoing.

The hazardous agent can include a pharmaceutically acceptable salt,solvate, hydrate, oxide or N-oxide thereof. In some embodiments, thehazardous agent is a hazardous agent or a pharmaceutically acceptablesalt, solvate, hydrate, oxide or N-oxide thereof. In some embodimentsthe hazardous agent is a compound of formula (I):

or a pharmaceutically acceptable salt, solvate, hydrate, oxide orN-oxide thereof. In some embodiments, the hazardous agent ismethotrexate.

In one aspect, the present disclosure relates to powered injectors forthe safe self injection of one or more hazardous agents in less thanabout 5 seconds. In various aspects, the powered injectors may beutilized by patients to self-inject hazardous agents. In certainembodiments, the powered injectors are needle assisted. In certainembodiments, the powered injectors are needle-free. In certainembodiments, the powered injectors may utilize pressure sufficient todeliver a therapeutically effective amount of one or more hazardousagents completely and quickly, in less than about 5 seconds. In certainembodiments, the powered injectors may comprise a pre-filled syringe forcontaining the one or more hazardous agents. In certain embodiments, thepowered injectors may comprise a syringe sleeve to contain thepre-filled syringe and to minimize syringe movement from injection forceto decrease syringe shock. In certain embodiments, the powered injectorsmay comprise a needle exposure control element. In certain embodiments,the powered injectors may comprise a safe means to prevent hazards afterinjection that may arise from the hazardous agents directly and/or frombody fluids contacted with hazardous agents. In certain embodiments, thepowered injectors may comprise a safe means to prevent hazards afterinjection that may arise from residual hazardous agents present ininjector components that contact the hazardous agents.

In another aspect, the present disclosure relates to methods for safelyinjecting one or more hazardous agents into a subject. In certainembodiments, the methods utilize a powered injection system having apre-filled syringe containing at least one hazardous agent that allowsthe subject to safely self-administer the agent in less than about 5seconds. In certain embodiments, the methods include using aspring-powered injection device comprising a needle with means tocontrol needle exposure during the injection such that the exposure issufficient to deliver one or more hazardous agents to the appropriatetissue site. In certain embodiments, the injector may have a springsufficiently powerful to deliver one or more hazardous agents in lessthan about 2 seconds. In certain embodiments, the injector may have asyringe sleeve that minimizes syringe movement as a result of theinjection spring action. In certain embodiments, the injector may havemeans for controlling needle exposure that locks following injection toprevent needle re-exposure. In certain embodiments, the injector mayhave a liquid tight cap that covers the means for controlling needleexposure, that allows for removal of the cap when preparing injector forinjection, and that locks to the injector when re-attached followinginjection to provide a sealed container.

In several aspects, the present disclosure relates to an injectionsystem. In various aspects, the injection system comprises a poweredinjector configured to inject one or more medicaments in less than about5 seconds, and one or more medicaments. In various aspects, the poweredinjector comprises a container configured to contain a medicament, adelivery member associated with the container for injecting themedicament, a firing mechanism configured to expel the medicament fromthe fluid chamber through the delivery member for injecting themedicament, an energy source associated with the firing mechanism topower the firing mechanism for causing the injection, and a triggermechanism associated with the firing mechanism to activate the firingmechanism. In some embodiments, the powered injector can be anautoinjector configured to inject one or more medicaments in less thanabout 5 seconds. In some embodiments, the powered injector can be a jetinjector. In some embodiments, the jet injector can be needle-assisted.In some embodiments, the jet injector can be needle-free.

In another aspect, the present disclosure relates to an injectionsystem, which can include a powered injector configured to inject one ormore hazardous agents in less than about 5 seconds, and one or morehazardous agents. One embodiment of a powered injector has a containerconfigured to contain a hazardous agent, a delivery member associatedwith the container for injecting the hazardous agent, a firing mechanismconfigured to expel the hazardous agent from the container through thedelivery member for injecting the medicament, an energy sourceassociated with the firing mechanism to power the firing mechanism forcausing the injection, and a trigger mechanism associated with thefiring mechanism to activate the firing mechanism. The powered injectorcan be a single-shot injector, and can be pre-filled with the hazardousagent, or alternatively can be fillable or take cartridges that can beloaded into the injector for firing. Other embodiments can haveadjustable dosages.

In another embodiment, the present disclosure relates to an injectionsystem which can include a jet injector and a compound of formula (I).One embodiment of a jet injector has a container configured to contain ahazardous agent comprising a compound of formula (I), a injection outletmember associated with the container and defining an injection outletconfigured for injecting the hazardous agent, a firing mechanismconfigured to expel the hazardous agent from the fluid chamber throughthe injection outlet for injecting the hazardous agent, an energy sourceassociated with the firing mechanism to power the firing mechanism jetinjecting the hazardous agent from the injection outlet, and a triggermechanism associated with the firing mechanism to activate the firingmechanism. The jet injector can be a single-shot injector, and can bepre-filled with the hazardous agent, or alternatively can be fillable ortake cartridges that can be loaded into the injector for firing. Otherembodiments have adjustable dosages. In some embodiments, the hazardousagent is methotrexate or a pharmaceutically acceptable salt, solvate,hydrate, oxide or N-oxide thereof.

In another embodiment the present disclosure relates to an injectionsystem for the treatment of inflammatory diseases. In one embodiment,the injection system includes a jet injector and a therapeuticallyeffective amount of a medicament, wherein the therapeutically effectiveamount of medicament is sufficient to treat an inflammatory disease. Inone embodiment, the jet injector has a container configured to containthe medicament; an injection outlet member associated with the containerfor injecting the medicament; a firing mechanism configured to expel themedicament from the fluid chamber through the outlet member forinjecting the medicament; an energy source associated with the firingmechanism to power the firing mechanism jet injecting the medicamentfrom the injection outlet; and a trigger mechanism associated with thefiring mechanism to activate the firing mechanism. In some embodiments,the medicament is a hazardous agent. In some embodiments, the medicamentis methotrexate or a pharmaceutically acceptable salt, solvate, hydrate,oxide or N-oxide thereof.

In another embodiment the present disclosure relates to kits. In oneembodiment, the kits can comprise a jet injector configured to inject atherapeutically effective amount of one or more hazardous agents lessthan about 5 seconds, a therapeutically effective amount of a hazardousagent, and instructions for using the jet injector and the hazardousagent. In some embodiments, the jet injector comprises a containerconfigured to contain the hazardous agent, an injection outlet memberassociated with the container for injecting the hazardous agent, afiring mechanism configured to expel the hazardous agent from the fluidchamber through the outlet member for injecting the hazardous agent, anenergy source associated with the firing mechanism to power the firingmechanism jet injecting the hazardous agent from the injection outlet,and a trigger mechanism associated with the firing mechanism to activatethe firing mechanism. In one embodiment, the kits comprise a jetinjector, a therapeutically effective amount of methotrexate containedin the jet injector, and instructions for using the jet injector toinject the methotrexate into a subject.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other objects, features and advantages of the disclosure willbe apparent from a consideration of the following non-limiting detaileddescription considered in conjunction with the drawing figures, inwhich:

FIG. 1 is a side view of an injection device according to an embodimentof the present disclosure;

FIG. 2 is a cross-sectional view of the injection device of FIG. 1 in asafety state taken along line A-A;

FIG. 3 is an enlarged view of a portion of the cross-section shown inFIG. 2;

FIGS. 4A and 4B are perspective views of a safety member used inconnection with the injection device of FIG. 1;

FIG. 5 is an additional cross-sectional view of the device of FIG. 1 inthe safety state;

FIG. 6A is a cross-sectional view of the injection device of FIG. 1 in aready state;

FIG. 6B is a cross-sectional view of the injection device of FIG. 1 atthe start of an injection state;

FIG. 6C is a cross-sectional view of the injection device of FIG. 1 atthe end of an injection state;

FIG. 6D is a cross-sectional view of the injection device of FIG. 1 in alocked state;

FIG. 7 is an exploded view of a portion of the trigger mechanismassociated with the injection device of FIG. 1;

FIG. 8 is a perspective view of a needle guard according to anembodiment of the injector of FIG. 1;

FIG. 9 is a cross-sectional view of the cap shown in FIG. 1;

FIG. 10 is a graph showing the pressure within the liquid chamber of anembodiment of an injection device according to the present disclosure,as a function of time;

FIG. 11 is a cross-sectional view of a needle-free jet injection nozzle;

FIG. 12 shows the pharmacokinetic profiles of methotrexate in Gottingenminipig plasma following subcutaneous injection of methotrexate with anembodiment of an autoinjector of the present disclosure as compared to aknown hypodermic syringe;

FIG. 13 shows the mean pharmacokinetic profiles of methotrexate inGottingen minipig plasma following subcutaneous injection ofmethotrexate with an embodiment of an autoinjector of the presentdisclosure as compared to a known hypodermic syringe;

FIG. 14 shows further mean pharmacokinetic profiles of methotrexate inGottingen minipig plasma following subcutaneous injection ofmethotrexate with an embodiment of an autoinjector of the presentdisclosure as compared to a known hypodermic syringe;

FIG. 15 shows a comparison of methotrexate exposure (C_(max) andAUC(0−t)) in Gottingen minipig plasma following subcutaneous injectionof methotrexate with an embodiment of an autoinjector of the presentdisclosure as compared to a known hypodermic syringe;

FIG. 16 shows a comparison of spring force during injection between anembodiment of an autoinjector of the present disclosure and a knownautoinjector.

DETAILED DESCRIPTION Definitions

“Acyl” refers to a radical —C(O)R, where R is hydrogen, alkyl,cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,heteroarylalkyl as defined herein. Representative examples include, butare not limited to formyl, acetyl, cylcohexylcarbonyl,cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl and the like.

“Acylamino” (or alternatively “acylamido”) refers to a radical—NR′C(O)R, where R′ and R are each independently hydrogen, alkyl,cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,heteroarylalkyl, as defined herein. Representative examples include, butare not limited to, formylamino, acetylamino (i.e., acetamido),cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino(i.e., benzamido), benzylcarbonylamino and the like.

“Alkoxy” refers to a radical —OR where R represents an alkyl orcycloalkyl group as defined herein. Representative examples include, butare not limited to, methoxy, ethoxy, propoxy, butoxy, cyclohexyloxy andthe like.

“Alkoxycarbonyl” refers to a radical —C(O)-alkoxy, where alkoxy is asdefined herein.

“Alkyl” refers to a saturated or unsaturated, branched, straight-chainor cyclic monovalent hydrocarbon radical derived by the removal of onehydrogen atom from a single carbon atom of a parent alkane, alkene oralkyne. Typical alkyl groups include, but are not limited to, methyl;ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan-1-yl,propan-2-yl, cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl,prop-2-en-1-yl (allyl), cycloprop-1-en-1-yl; cycloprop-2-en-1-yl,prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butyls such as butan-1-yl,butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl,but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl,but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.

The term “alkyl” is specifically intended to include groups having anydegree or level of saturation, i.e., groups having exclusively singlecarbon-carbon bonds, groups having one or more double carbon-carbonbonds, groups having one or more triple carbon-carbon bonds and groupshaving mixtures of single, double and triple carbon-carbon bonds. Wherea specific level of saturation is intended, the expressions “alkanyl,”“alkenyl,” and “alkynyl” are used. In some embodiments, an alkyl groupcomprises from 1 to 20 carbon atoms, in some embodiments, from 1 to 10carbon atoms.

“Alkylamino” means a radical —NHR where R represents an alkyl orcycloalkyl group as defined herein. Representative examples include, butare not limited to, methylamino, ethylamino, 1-methylethylamino,cyclohexyl amino and the like.

“Alkylsulfinyl” refers to a radical —S(O)R where R is an alkyl orcycloalkyl group as defined herein. Representative examples include, butare not limited to, methylsulfinyl, ethylsulfinyl, propylsulfinyl,butylsulfinyl and the like.

“Alkylsulfonyl” refers to a radical —S(O)₂R where R is an alkyl orcycloalkyl group as defined herein. Representative examples include, butare not limited to, methylsulfonyl, ethylsulfonyl, propylsulfonyl,butylsulfonyl and the like.

“Alkylthio” refers to a radical —SR where R is an alkyl or cycloalkylgroup as defined herein. Representative examples include, but are notlimited to methylthio, ethylthio, propylthio, butylthio and the like.

“Amino” refers to the radical —NH2.

“Aryl” refers to a monovalent aromatic hydrocarbon group derived by theremoval of one hydrogen atom from a single carbon atom of a parentaromatic ring system. Typical aryl groups include, but are not limitedto, groups derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexylene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, triphenylene, trinaphthalene and the like. In someembodiments, an aryl group comprises from 6 to 20 carbon atoms, in someembodiments between 6 to 12 carbon atoms.

“Arylalkyl” refers to an acyclic alkyl group in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom, is replaced with an aryl group. Typical arylalkyl groupsinclude, but are not limited to, benzyl, 2-phenylethan-1-yl,2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl,2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and thelike. Where specific alkyl moieties are intended, the nomenclaturearylalkanyl, arylalkenyl and/or arylalkynyl is used. In someembodiments, an arylalkyl group is (C₆-C₃₀)arylalkyl, e.g., the alkanyl,alkenyl or alkynyl moiety of the arylalkyl group is (C₁-C₁₀) and thearyl moiety is (C₆-C₂₀), in some embodiments, an arylalkyl group is(C₆-C₂₀)arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of thearylalkyl group is (C₁-C₈) and the aryl moiety is (C₆-C₁₂).

“Aryloxy” refers to a radical —OR where R represents an aryl group asdefined herein.

“AUC” is the area under a curve representing the concentration of acompound, such as a hazardous agent as defined herein, or metabolitethereof in the blood or plasma of a patient as a function of timefollowing administration of the compound to the patient. For example,the administered compound can be a hazardous agent as defined herein.The AUC may be determined by measuring the concentration of a compoundor metabolite thereof in blood using methods such as liquidchromatography-tandem mass spectrometry (LC/MS/MS), at various timeintervals, and calculating the area under the blood or plasmaconcentration-versus-time curve. The concentration versus time curve isalso referred to as the pharmacokinetic profile. Suitable methods forcalculating the AUC from a compound concentration-versus-time curve arewell known in the art. For example, an AUC for the hazardous agentmethotrexate may be determined by measuring the concentration ofmethotrexate in the blood of a patient following administration ofmethotrexate to the patient. AUC₀₋₂₄ is the area under the curve fromadministration (time 0) to 24 hours following administration.AUC_(ss,24) is the area under the curve over a 24 hour period followinga dosing regimen administered over a period of days (steady state).

“Bioavailability” refers to the amount of a compound, such as, forexample, a hazardous agent, that reaches the systemic circulation of apatient following administration of the compound to the patient and canbe determined by evaluating, for example, the blood or plasmaconcentration for the compound. For example, the administered compoundcan be a hazardous agent as defined herein.

“Compounds” of the present disclosure include compounds within the scopeof formula (I). Compounds may be identified either by their chemicalstructure and/or chemical name. When the chemical structure and chemicalname conflict, the chemical structure is determinative of the identityof the compound. The compounds described herein may comprise one or morechiral centers and/or double bonds and therefore may exist asstereoisomers such as double-bond isomers (i.e., geometric isomers),enantiomers, or diastereomers. Accordingly, unless specificallyindicated, any chemical structures within the scope of the specificationdepicted, in whole or in part, with a relative configuration encompassall possible enantiomers and stereoisomers of the illustrated compoundsincluding the stereoisomerically pure form (e.g., geometrically pure,enantiomerically pure, or diastereomerically pure) and enantiomeric andstereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures may beresolved into their component enantiomers or stereoisomers usingseparation techniques or chiral synthesis techniques well known to theskilled artisan. For example, resolution of the enantiomers ordiastereomers may be accomplished by conventional methods such ascrystallization in the presence of a resolving agent, or chromatography,using a chiral high-pressure liquid chromatography (HPLC) column.

The compounds as disclosed herein may also exist in several tautomericforms including the enol form, the keto form, and mixtures thereof.Accordingly, the chemical structure depicted herein encompasses allpossible tautomeric forms of the illustrated compounds. Compounds of thepresent disclosure also include isotopically labeled compounds where oneor more atoms have an atomic mass different from the atomic massconventionally found in nature. Examples of isotopes that may beincorporated into the compounds disclosed herein include, but are notlimited to, ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, etc. Compounds mayexist in unsolvated forms as well as solvated forms, including hydratedforms and as oxides or N-oxides. In general, compounds may be free acid,hydrated, solvated, oxides, or N-oxides. Compounds may exist in multiplecrystalline, co-crystalline, or amorphous forms. Compounds includepharmaceutically acceptable salts thereof, or pharmaceuticallyacceptable solvates of the free acid form of any of the foregoing, aswell as crystalline forms of any of the foregoing. Compounds alsoinclude solvates.

“Cycloalkyl” refers to a saturated or unsaturated cyclic alkyl radical.Where a specific level of saturation is intended, the nomenclature“cycloalkanyl” or “cycloalkenyl” is used. Typical cycloalkyl groupsinclude, but are not limited to, groups derived from cyclopropane,cyclobutane, cyclopentane, cyclohexane, and the like. In someembodiments, the cycloalkyl group is (C₃-C₁₀)cycloalkyl, in someembodiments (C₃-C₇)cycloalkyl.

“Cycloheteroalkyl” refers to a saturated or unsaturated cyclic alkylradical in which one or more carbon atoms (and any associated hydrogenatoms) are independently replaced with the same or different heteroatom.Typical heteroatoms to replace the carbon atom(s) include, but are notlimited to, N, P, O, S, Si, etc. Where a specific level of saturation isintended, the nomenclature “cycloheteroalkanyl” or “cycloheteroalkenyl”is used. Typical cycloheteroalkyl groups include, but are not limitedto, groups derived from epoxides, imidazolidine, morpholine, piperazine,piperidine, pyrazolidine, pyrrolidine, quinuclidine, and the like.

“Dialkylamino” means a radical —NRR′ where R and R′ independentlyrepresent an alkyl or cycloalkyl group as defined herein. Representativeexamples include, but are not limited to, dimethylamino,methylethylamino, di-(1-methylethyl)amino, (cyclohexyl)(methyl)amino,(cyclohexyl)(ethyl)amino, (cyclohexyl)(propyl)amino and the like.

“Formula (I)” includes the methotrexate derivative (I), pharmaceuticallyacceptable salts thereof, pharmaceutically acceptable solvates of any ofthe foregoing, pharmaceutically acceptable hydrates of any of theforegoing, pharmaceutically acceptable oxides of any of the foregoing,and crystalline forms of any of the foregoing. Formula (I) is usedinterchangeably with a compound of formula (I). In certain embodiments,a compound of formula (I) can be a free acid. In certain embodiments, acompound of formula (I) can be a pharmaceutically acceptable salt.

“Halo” means fluoro, chloro, bromo, or iodo.

“Hazardous Agent(s)” means any one or more medications that are toxicagents, cytotoxic agents and/or other dangerous agents that may causeserious effects upon contact with a subject as well as highly potentagents, agents that have profound physiological effects at low doses,analgesics, immunomodulating agents, IL-1 receptor antagonists, IL-2alpha receptor antagonists, anti-rejection compounds, hormonal agents,prostaglandins, sedatives, anticholinergic agents, Parkinsons diseasedrugs, expensive agents, neuroleptic agents, tissue necrosis factor(TNF) blockers, and other dangerous agents. In this disclosure, the term“hazardous agent(s)” is used interchangeably with “agent” and“medicament”. Hazardous agents include, without limitation,antineoplastic cytotoxic medications, anesthetic agents, anti-viralagents, potent peptide compounds, toxic agents, cytotoxic agents, highlypotent agents, agents that have profound physiological effects at lowdoses, analgesics, immunomodulating agents, IL-1 receptor antagonists,IL-2 alpha receptor antagonists, anti-rejection compounds, hormonalagents, prostaglandins, sedatives, anticholinergic agents, Parkinsonsdisease drugs, expensive agents, neuroleptic agents, tissue necrosisfactor (TNF) blockers, and other dangerous agents. toxic agents,cytotoxic agents, highly potent agents, agents that have profoundphysiological effects at low doses and other dangerous agents.

Examples of highly potent agents include, without limitation, steroidssuch as dexamethasone, progesterone, somatostatin, and analoguesthereof; biologically active peptides such as teriparatide; andanticholinergics such as scopolamine. Examples of agents that haveprofound physiological effects at low doses include, without limitation,antihypertensives and/or blood pressure down regulators. Examples ofanalgesics include, without limitation, fentanyl, fentanyl citrate,morphine, meperidine, and other opioids. Examples of immunomodulatingagents include, without limitation, adalimumab (anti-tissue necrosisfactor monoclonal antibody or anti-TNF). Examples of IL-1 receptorantagonists include, without limitation, anakinra. Examples of IL-2alpha receptor antagonists include, without limitation, daclizumab andbasiliximab. Examples of anti-rejection compounds include, withoutlimitation, azathioprine, cyclosporine, and tacrolimus. Examples ofhormonal agents include, without limitation, testosterone, estrogen,growth hormone, insulin, thyroid hormone, follicle stimulating hormone(FSH), epinephrine/adrenaline, progesterone, parathyroid hormone,gonadotrophin releasing hormone (GHRH), leutinizing hormone releasinghormone (LHRH), other hormones such as those where contact with thehormone by members of the opposite sex can lead to side effects, andderivatives thereof. Examples of prostaglandins include, withoutlimitation, gamma-linolenic acid, docosahexanoic acid, arachidonic acidand eicosapentaenoic acid. Examples of sedatives include, withoutlimitation, barbiturates such as amobarbital, pentobarbital,secobarbital, and phenobarbitol; benzodiazepines such as clonazepam,diazepam, estazolam, flunitrazepam, lorazepam, midazolam, nitrazepam,oxazepam, triazolam, temazepam, chlordiazepoxide, and alprazolam; herbalsedatives such as ashwagandha, duboisia hopwoodii, prosantherastriatiflora, kava (piper methysticum), mandrake, valerian, andmarijuana; non-benzodiazepine sedatives (a.k.a. “Z-drugs”) such aseszopiclone, zaleplon, zolpidem, zopiclone; antihistamines such asdiphenhydramine, dimenhydrinate, doxylamine, and promethazine; and othersedatives such as chloral hydrate. Examples of anticholinergic agentsinclude, without limitation, dicyclomine, atropine, ipratropium bromide,oxitropium bromide, and tiotropium. Examples of Parkinson's diseasedrugs include, without limitation, levodopa, dopamine, carbidopa,benserazide, co-ceraldopa, co-beneldopa, tolcapone, entacapone,bromocriptine, pergolide, pramipexole, ropinirole, piribedil,cabergoline, apomorphine, and lisuride. Examples of expensive agentsinclude, without limitation, human growth hormone and erythropoietin.Examples of neuroleptic agents includes, without limitation,antipsychotics; butyrophenones such as haloperidol and droperidol;phenothiazines such as chlorpromazine, fluphenazine, perphenazine,prochlorperazine, thioridazine, trifluoperazine, mesoridazine,periciazine, promazine, triflupromazine, levomepromazine, promethazine,and pimozide; thioxanthenes such as chlorprothixene, clopenthixol,flupenthixol, thiothixene, and zuclopenthixol; atypical antipsychoticssuch as clozapine, olanzapine, risperidone, quetiapine, ziprasidone,amisulpride, asenapine, paliperidone, iloperidone, zotepine, andsertindole; and third generation antipsychotics such as aripiprazole andbifeprunox. Examples of TNF blockers includes, without limitation,etanercept.

Hazardous agents include pharmaceutically acceptable salts, solvates,hydrates, oxides or N-oxides. In some embodiments the hazardous agent isa cytotoxic compound or a pharmaceutically acceptable salt, solvate,hydrate, oxide or N-oxide thereof. In some embodiments the hazardousagent is a compound of formula (I):

-   -   or a pharmaceutically acceptable salt, solvate, hydrate, oxide        or N-oxide thereof. In some embodiments, the medicament is        methotrexate.

In some embodiments, the hazardous agent can be selected from botulinumtoxin, injectable gold, 6-mercaptopurine, 6-thioinosinic acid,azathioprine, chlorambucil, cyclophosphamide, cytophosphane, cytarabine,fluorouracil, melphalan, methotrexate, uramustine, anti-cytokinebiologicals, cell receptor antagonists, cell receptor analogues,dexamethasone, progesterone, somatostatin, analogues of dexamethasone,analogues of progesterone, analogues of somatostatin, teriparatide,scopolamine, antihypertensives, blood pressure down regulators,fentanyl, fentanyl citrate, morphine, meperidine, other opioids,adalimumab (anti-tissue necrosis factor monoclonal antibody oranti-TNF), anakinra, daclizumab, basiliximab, azathioprine,cyclosporine, tacrolimus, testosterone, estrogen, growth hormone,insulin, thyroid hormone, follicle stimulating hormone (FSH),epinephrine/adrenaline, gamma-linolenic acid, docosahexanoic acid,arachidonic acid, eicosapentaenoic acid, amobarbital, pentobarbital,secobarbital, phenobarbitol, clonazepam, diazepam, estazolam,flunitrazepam, lorazepam, midazolam, nitrazepam, oxazepam, triazolam,temazepam, chlordiazepoxide, alprazolam, ashwagandha, duboisiahopwoodii, prosanthera striatiflora, kava (piper methysticum), mandrake,valerian, marijuana, eszopiclone, zaleplon, zolpidem, zopiclone,diphenhydramine, dimenhydrinate, doxylamine, promethazine, chloralhydrate, dicyclomine, atropine, ipratropium bromide, oxitropium bromide,tiotropium, levodopa, dopamine, carbidopa, benserazide, co-ceraldopa,co-beneldopa, tolcapone, entacapone, bromocriptine, pergolide,pramipexole, ropinirole, piribedil, cabergoline, apomorphine, lisuride,human growth hormone, erythropoietin, haloperidol, droperidol,chlorpromazine, fluphenazine, perphenazine, prochlorperazine,thioridazine, trifluoperazine, mesoridazine, periciazine, promazine,triflupromazine, levomepromazine, promethazine, pimozide,chlorprothixene, clopenthixol, flupenthixol, thiothixene,zuclopenthixol, clozapine, olanzapine, risperidone, quetiapine,ziprasidone, amisulpride, asenapine, paliperidone, iloperidone,zotepine, sertindole, aripiprazole, bifeprunox, etanercept, derivativesof any of the foregoing, and combinations of any of the foregoing.

Hazardous agents are capable of causing mortality and/or serious effectsincluding cancer, infections, organ toxicity, fertility problems,genetic damage, and birth defects. Hazardous agents can also possessmechanisms of action that are acutely less serious, but stillpotentially deleterious to the patient, such as suppression of theimmune system. The suppression occurs by down regulation of a populationor activity of specific cells that participate in the immune response,which increases susceptibility to infection. However, even thoughsuppression of the immune system is potentially deleterious, it can alsoact to reduce inflammation in a subject, thereby providing a benefit topatients with autoimmune diseases.

“Heteroalkyloxy” means an —O-heteroalkyl group where heteroalkyl is asdefined herein.

“Heteroalkyl” refers to alkyl, alkanyl, alkenyl and alkynyl radical,respectively, in which one or more of the carbon atoms (and anyassociated hydrogen atoms) are each independently replaced with the sameor different heteroatomic groups. Typical heteroatomic groups include,but are not limited to, -0-, —S—, -0-0-, —S—S—, -0-S—, —NR′—, ═N—N═,—N═N—, —N═N—NR′—, —PH—, —P(O)₂—, —O—P(O)₂—, —S(O)—, —S(O)₂—, —SnH₂—, andthe like, where R′ is hydrogen, alkyl, cycloalkyl, or aryl.

“Heteroaryl” refers to a monovalent heteroaromatic radical derived bythe removal of one hydrogen atom from a single atom of a parentheteroaromatic ring system. Typical heteroaryl groups include, but arenot limited to, groups derived from acridine, arsindole, carbazole,P-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole,indole, indoline, indolizine, isobenzofuran, isochromene, isoindole,isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine,oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline,phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline,quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole,thiophene, triazole, xanthene, and the like. In some embodiments, theheteroaryl group is between 5-20 membered heteroaryl, in someembodiments between 5-10 membered heteroaryl. In some embodimentsheteroaryl groups can be those derived from thiophene, pyrrole,benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole,oxazole and pyrazine.

“Heteroarylalkyl” refers to an acyclic alkyl group in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom, is replaced with a heteroaryl group. Where specific alkylmoieties are intended, the nomenclature heteroarylalkanyl,heteroarylalkenyl and/or heterorylalkynyl is used. In some embodiments,the heteroarylalkyl group is a 6-30 membered heteroarylalkyl, e.g., thealkanyl, alkenyl or alkynyl moiety of the heteroarylalkyl is 1-10membered and the heteroaryl moiety is a 5-20 membered heteroaryl, insome embodiments, 6-20 membered heteroarylalkyl, e.g., the alkanyl,alkenyl or alkynyl moiety of the heteroarylalkyl is 1-8 membered and theheteroaryl moiety is a 5-12-membered heteroaryl.

“Heteroaryloxy” means an —O-heteroaryl group where heteroaryl is asdefined herein.

“N-oxide” (also known as “amine oxide” and “amine-N-oxide”) refers to achemical compound that contains the functional group R₃N⁺—O⁻, where R ishydrogen, alkyl, aryl, arylalkyl, cycloalkyl, cycloheteroalkyl,heteroalkyl, heteroaryl, or heteroarylalkyl.

“Oxide” refers to a chemical compound containing at least one oxygenatom as well as at least one other element.

“Patient” and “Subject” both independently include mammals, such as forexample, humans.

“Pharmaceutically acceptable” refers to approved or approvable by aregulatory agency of a federal or a state government, listed in the U.S.Pharmacopeia, or listed in other generally recognized pharmacopeia foruse in mammals, including humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound, suchas a salt of a hazardous agent, that is pharmaceutically acceptable andthat possesses the desired pharmacological activity of the parentcompound. Such salts include: (1) acid addition salts that are formedwith inorganic acids such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like; or that areformed with organic acids such as acetic acid, propionic acid, hexanoicacid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lacticacid, malonic acid, succinic acid, malic acid, maleic acid, fumaricacid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; and (2)salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthmetal ion, or an aluminum ion; or coordinates with an organic base suchas ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, andthe like. In certain embodiments, a salt of a hazardous agent is thehydrochloride salt, and in certain embodiments, the sodium salt.

“Pharmaceutically acceptable vehicle” or “pharmaceutically acceptableexcipient” refers to a pharmaceutically acceptable diluent, apharmaceutically acceptable adjuvant, a pharmaceutically acceptableexcipient, a pharmaceutically acceptable carrier, or a combination ofany of the foregoing with which a compound, such as, for example, ahazardous agent, may be administered to a patient, which does notdestroy the pharmacological activity thereof, and which is nontoxic whenadministered in doses sufficient to provide a therapeutically effectiveamount of the compound.

“Pharmacokinetics” refers to the assessment of the fate of anadministered medication in the body. Parameters useful in characterizingpharmacokinetics include a blood concentration-versus-time curve includethe area under the curve (AUC), the time to peak concentration(T_(max)), and the maximum compound concentration C_(max), where C_(max)is the maximum concentration of a compound in the blood plasma of apatient following administration of a dose of the compound to thepatient, and T_(max) is the time to the maximum concentration (C_(max))of a compound in the blood or plasma of a patient followingadministration of a dose of the compound to the patient.

“Powered injectors” are injection devices that have an energy sourcethat powers a mechanism to fire the injector. Powered injectors of thepresent disclosure are configured to deliver, or inject, one or morehazardous agents into a subject in less than about 5 seconds.

“Solvate” refers to a molecular complex of a compound with one or moresolvent molecules in a stoichiometric or non-stoichiometric amount. Suchsolvent molecules are those commonly used in the pharmaceutical art,which are known to be innocuous to a patient, e.g., water, ethanol, andthe like. A molecular complex of a compound or moiety of a compound anda solvent can be stabilized by non-covalent intra-molecular forces suchas, for example, electrostatic forces, van der Waals forces, or hydrogenbonds. The term “hydrate” refers to a solvate in which the one or moresolvent molecules is water.

“Therapeutically effective amount” refers to the amount of a hazardousagent that, when administered to a subject for treating a disease ordisorder, or at least one of the clinical symptoms of a disease ordisorder, is sufficient to affect such treatment of the disease,disorder, or symptom. The therapeutically effective amount may varydepending, for example, on the compound, the disease, disorder, and/orsymptoms of the disease, severity of the disease or disorder, and/orsymptoms of the disease or disorder, the age, weight, and/or health ofthe patient to be treated, and the judgment of the prescribingphysician. A therapeutically effective amount may be ascertained bythose skilled in the art or capable of determination by routineexperimentation.

“Treating” or “treatment” of any disease refers to arresting orameliorating a disease or disorder, or at least one of the clinicalsymptoms of a disease or disorder, reducing the risk of acquiring adisease or disorder or at least one of the clinical symptoms of adisease or disorder, reducing the development of a disease or disorder,or at least one of the clinical symptoms of the disease or disorder, orreducing the risk of developing a disease or disorder, or at least oneof the clinical symptoms of a disease or disorder. “Treating” or“treatment” also refers to inhibiting the disease or disorder, eitherphysically, (e.g., stabilization of a discernible symptom),physiologically, (e.g., stabilization of a physical parameter), or both,and to inhibiting at least one physical parameter that may or may not bediscernible to the patient. In certain embodiments, “treating” or“treatment” refers to delaying the onset of the disease or at least oneor more symptoms thereof in a patient which may be exposed to orpredisposed to a disease or disorder even though that patient does notyet experience or display symptoms of the disease.

Reference is now made in detail to certain embodiments of the disclosureincluding, without limitation, hazardous agents, injectors and methods.The disclosed embodiments are not intended to be limiting of the claims.To the contrary, the claims are intended to cover all alternatives,modifications, and equivalents.

Injection of Hazardous Agents

In various aspects, the present disclosure relates to the injection ofhazardous agents. In some embodiments, the hazardous agents arecytotoxic agents. Examples of cytotoxic agents that may be usedaccording to the present disclosure include, without limitation,6-mercaptopurine, 6-thioinosinic acid, azathioprine, chlorambucil,cyclophosphamide, cytophosphane, cytarabine, melphalan, methotrexate,uramustine, anti-tissue necrosis factor biologicals, anti-cytokinebiologicals, cell receptor antagonists, cell receptor analogues, andderivatives of each of the foregoing. Some of these agents are labeled“cytotoxic” because they act by directly killing cells or by impedingcell metabolism. Cytotoxic agents acting in this manner elicit theirgreatest effect against rapidly dividing cells. In the case of rapidlydividing tumor cells, cytotoxic agents are particularly effectivebecause they act to kill these cells. This activity can also suppressthe cells involved in a hyperactive immune response, resulting in areduction in disease activity, which enables cytotoxic agents to treatdiseases such as rheumatoid arthritis (and other autoimmune diseases),lupus, vasculitis and related conditions. The base mechanism of actionis the suppression of a hyperactive immune response, which results inanti-inflammatory effects. For example, when used at low doses to treatsuch diseases, the method of action of the cytotoxic agent methotrexateis anti-inflammatory, not cytotoxic.

In some embodiments, one or more hazardous agents and/orpharmaceutically acceptable salts, solvates, hydrates, oxides andN-oxides thereof, can be injected in less than about 5 seconds via theuse of a powered injector. In some embodiments, the present disclosurerelates to the injection of one or more hazardous agents and one or morepharmaceutically acceptable excipients. In some embodiments, the presentdisclosure relates to the injection of a pharmaceutically acceptablesalt of one or more hazardous agents.

Injection of Methotrexate and its Derivatives

In some embodiments, the injected hazardous agent is methotrexate and/orone or more derivatives of methotrexate as given by formula (I),described further below. In one aspect, the present disclosure relatesto the injection of methotrexate and/or derivatives of methotrexate viaa powered injector in less than about 5 seconds. In some embodiments,methotrexate and/or derivatives of methotrexate and/or pharmaceuticallyacceptable salts, solvates, hydrates, oxides and N-oxides thereof, areinjected. In some embodiments, the present disclosure relates to theinjection of methotrexate and/or derivatives of methotrexate and one ormore pharmaceutically acceptable excipients. In some embodiments, thepresent disclosure relates to the injection of a pharmaceuticallyacceptable salt of methotrexate and/or derivatives of methotrexate. Insome embodiments, the present disclosure relates to the injection ofpharmaceutical compositions comprising methotrexate and apharmaceutically acceptable excipient.

Jet Injection of Hazardous Agents

In some embodiments, the present disclosure relates to the injection ofhazardous agents via a jet injector. In some embodiments, the jetinjector is a needle-assisted jet injector. In some embodiments, the jetinjector is a needle-free jet injector. In some embodiments, hazardousagents and/or pharmaceutically acceptable salts, solvates, hydrates,oxides and N-oxides thereof, are injected. In some embodiments,pharmaceutical compositions comprising one or more hazardous agents andone or more pharmaceutically acceptable excipients are injected. In someembodiments, a pharmaceutically acceptable salt of a hazardous agent isinjected. In some embodiments, the present disclosure relates to theinjection of pharmaceutical compositions comprising methotrexate and apharmaceutically acceptable excipient.

Compounds

In various aspects, the present disclosure relates to hazardous agents.In various embodiments, the present disclosure relates to compounds offormula (I):

and pharmaceutically acceptable salts, solvates, hydrates, oxides andN-oxides thereof.

In various aspects, R₁, R₂, and R₃ are independently selected from thegroup hydrogen, alkyl, alkoxy, acyl, acylamino, alkylamino,alklysulfinyl, alkylsulfonyl, alkylthio, alkoxycarbonyl, aryl,arylalkyl, aryloxy, cycloalkyl, cycloheteroalkyl, dialkylamino, halo,heteroalkyl, heteroaryl, heteroarylalkyl, heteroalkyloxy, andheteroaryloxy.

In certain embodiments, the compound of formula (I) is the cytotoxicagent methotrexate, wherein R₁ is methyl and R₂ and R₃ are bothhydrogen. Chemically, methotrexate is known asL-(+)-N-[p-[[(2,4-Diamino-6-pteridinyl)methyl]methylamino]-benzoyl]glutamicacid or by its systematic (IUPAC) name(2S)-2-[(4-{[(2,4-diamino-7,8-dihydropteridin-6-yl)methyl](methyl)amino}phenyl)formamido]pentanedioicacid.

In certain embodiments, compounds of formula (I) may be prepared usingthe methods described by U.S. Pat. No. 4,374,987 to Singh et al. and/orU.S. Pat. No. 4,080,325 to Ellard.

The hazardous agents of the present disclosure can comprise atherapeutically effective amount of one or more of the hazardous agentsdisclosed herein, in some embodiments in purified form, together with asuitable amount of a pharmaceutically acceptable vehicle, so as toprovide the form for proper self administration by a patient. In someembodiments, when self administered by a patient, the hazardous agentsof the present disclosure and pharmaceutically acceptable vehicles aresterile. In some embodiments, water can be used as a vehicle when thehazardous agents of the present disclosure are self injected. In someembodiments, saline solutions and aqueous dextrose and glycerolsolutions can also be employed as liquid vehicles for injectablesolutions. Suitable pharmaceutical vehicles can also include excipientssuch as sodium phosphate, sodium citrate, sodium acetate trihydrate,citric acid, glacial acetic acid, mannitol, polysorbate 80, L-argininehydrochloride, metacresol, phenol, zinc oxide, and water. In someembodiments, hazardous agents of the present disclosure can also containminor amounts of wetting or emulsifying agents, pH buffering agents,and/or auxiliary, stabilizing, thickening, lubricating and/or coloringagents.

In some embodiments, pharmaceutical compositions provided by the presentdisclosure comprise the hazardous agents disclosed herein together withone or more pharmaceutically acceptable excipients.

The amount of the one or more pharmaceutically acceptable excipients ina pharmaceutical composition can be, for example: from about 0.005% w/vto about 10% w/v; and from about 2% w/v to about 6% w/v; where % w/v isbased on the total weight of the excipient per unit volume.

In some embodiments, pharmaceutical compositions provided by the presentdisclosure comprise a pharmaceutically acceptable salt of the hazardousagents disclosed herein.

Pharmacokinetics

Typically, the bioavailability of a hazardous agent is close to 100%when it is injected or administered intravenously because the hazardousagent does not get destroyed in the gastrointestinal tract and clearedfrom the subject's body or, if the hazardous agent is injected into atissue, it does not have any tissue architecture or constituents totraverse prior to being systemically available. By changing the way thehazardous agent is administered, the pharmacokinetics of that hazardousagent may also be altered in order to maintain the pharmacokineticsand/or bioavailability of the hazardous agent in a particular mannersuitable for a patient, dose or other hazardous agent property.

In some embodiments, the bioavailability of a hazardous agent can bemaintained, or approximated to a known or desired level, by selectingone or more factors in the configuration of a powered injector, and insome embodiments one or more factors in the configuration of a jetinjector, to maintain bioequivalence for the hazardous agent.Bioequivalence can be measured using means known in the art to measureplasma levels to determine the rate and extent of absorption of thehazardous agent and determining the AUC for the hazardous agent todetermine the extent of absorption. C_(max) concentrations may also beused to determine the rate of hazardous agent absorption. Bioequivalenceis established if a hazardous agent injected via an injector of thepresent disclosure reaches the site of absorption in similar times andis absorbed to the same extent as if the hazardous agent had beenintroduced to the subject via other known routes of administration.Typically, bioequivalence of a hazardous agent is reached if one or moreconfidence intervals of the measured pharmacokinetic parameters fallbetween about 80% and about 125% of a known or desired level of thehazardous agent (see: Approved Compound Products With TherapeuticEquivalence Evaluations, US Food and Compound Administration ElectronicOrange Book, 27th ed. Washington, D.C.: US Department of Health & HumanServices (2007); and 21 C.F.R. §320.33 (Apr. 1, 2005)).

The rate of injection, or the speed at which a hazardous agent isdelivered to a subject, is a function of several features of theinjector used, and can include, without limitation, the pressureutilized by the injector to make the injection, and/or the configurationand dimensions of the injection outlet of an injection outlet member inan injector, such as the needle used or the needle-free nozzle. In someembodiments, the speed of injection of an injector can be selected tomaintain the pharmacokinetics and/or bioavailability of a hazardousagent at a level that is similar to other methods of parenteral deliveryincluding, without limitation, traditional hypodermic-syringe injection,by altering the pressure used in the injector to jet inject thehazardous agent.

Changes in one or more factors in the configuration of an injector maybe necessary because the interactions of the hazardous agent, onceejected from an injector of the present disclosure, can vary widely fromsubject to subject. It is believed that the deposition pattern of thehazardous agent resulting from injection is noteworthy as increaseddispersion from a powered injector, as compared to bolus deposition froma manual syringe, may impact the hazardous agent's interaction withcells and either enhance or impede the migration of the hazardous agentto the systemic circulation. For example, for the hazardous agentmethotrexate, cell transport mechanisms exist that result inmethotrexate uptake by cells, including the reduced folate carrier andmembrane transport proteins termed folate receptors. These mechanismshave variable rates of action and variable degrees of expression (seeKremer, J. M., Toward a better understanding of methotrexate, Arthritisand Rheumatism 2004; 50: 1370-1382). Since it is likely thatmethotrexate would encounter such cells after injection but beforereaching the systemic circulation, the pharmacokinetics and/orbioavailability of methotrexate resulting from the injection can varygreatly from individual to individual, thereby necessitating a change inthe manner in which methotrexate is administered from subject tosubject. The amount of change to one or more factors in theconfiguration of an injector will therefore depend, at least in part, onthe nature of the disease, the subject to be treated and the discretionof the prescribing physician, and may be determined by standardtechniques known in the art.

By using a powered injector of the present disclosure, a hazardous agentmay be injected into a subject more precisely and completely than if itwere injected via a manual syringe, and in less than about 5 seconds. Ina jet injector embodiment, the configuration of the jet injector, andthe factors affecting the injection, can be selected to obtain a C_(max)for a hazardous agent that is the same or substantially the same as thatseen with other methods of parenteral delivery including, withoutlimitation, a typical hand-powered hypodermic syringe. In another jetinjector embodiment, the configuration of the injector, and the factorsaffecting the injection, can be selected to obtain a T_(max) for ahazardous agent that is the same or substantially the same as that seenwith other methods of parenteral delivery including, without limitation,a typical hand-powered hypodermic syringe. In a further jet injectorembodiment, the configuration of the jet injector, and the factorsaffecting the injection, can be selected to obtain both a C_(max) and aT_(max) for a hazardous agent that is the same or substantially the sameas that seen with other methods of parenteral delivery including,without limitation, a typical hand-powered hypodermic syringe.

The pharmacokinetics of the cytotoxic agent methotrexate will now bedescribed as a specific example of the pharmacokinetics of the disclosedhazardous agents.

The pharmacokinetics of injected methotrexate are generally known (see,e.g., Aquerreta, I., et al., Ped. Blood & Cancer (2003); 42(1), 52-58;and Seideman, P., et al., Br. J. Clin. Pharmacol. (1993) April; 35(4):409-412). Methotrexate is a weak dicarboxylic acid with an aciddissociation constant of about 4.8 to about 5.5, and thus exists mostlyin its ionized state at physiologic pH. After intravenousadministration, the initial average distribution volume of methotrexateis typically about 0.18 L/kg (or about 18% of the subject's body weight)and the average steady-state distribution volume typically ranges fromabout 0.4 L/kg to about 0.8 L/kg (or about 40% to about 80% of thesubject's body weight). Methotrexate is generally completely absorbedfrom parenteral routes of injection. After intramuscular injection ofmethotrexate, peak serum concentrations (C_(max)) occur in about 30 toabout 60 minutes (T_(max)) in most patients. However, individual plasmaconcentrations of injected methotrexate have been reported to varywidely between individual subjects. For example, in pediatric patientswith juvenile rheumatoid arthritis, the average mean serumconcentrations of methotrexate were about 0.59 μM (averaged over a rangeof about 0.03 M to about 1.40 M) at about 1 hour, an average of about0.44 μM (averaged over a range of about 0.01 μM to about 1.00 μM) atabout 2 hours, and an average of about 0.29 μM (averaged over a range ofabout 0.06 μM to about 0.58 μM) at about 3 hours. In pediatric patientsreceiving methotrexate injections for acute lymphocytic leukemia (atdoses of about 6.3 mg/m² to about 30 mg/m²) or for juvenile rheumatoidarthritis (at doses of about 3.75 mg/m² to about 26.2 mg/m²), theterminal half-life of methotrexate has been reported to range from about0.7 hours to about 5.8 hours, or from about 0.9 hours to about 2.3hours, respectively.

Toxicity at Higher Doses

As shown by several prior studies, it is presently unclear whetherincreasing a regular dose of methotrexate results in an increase incompound efficacy. What is clear, however, is that as the dose ofmethotrexate increases, toxicity-associated side effects also increase.For example, Furst et al. evaluated the effect of increasing oral dosesof methotrexate from 5 mg/m² (7.5 mg to 10 mg) per week to 10 mg/m² (15mg to 22 mg) per week in 46 patients (see Furst, D. E., et al., J.Rheumatol., 1989; 16: 313-320). In this study, the authors noted thathigher doses of methotrexate resulted in a dose-related efficacyresponse together with a trend toward increased toxicity. However, aseparate study conducted by Lambert et al. did not find improvedefficacy with increasing doses of methotrexate (see Lambert, C. M., etal., Arthritis and Rheumatism, 2004; 50: 364-371). In this study, theeffect of escalating intramuscular methotrexate dosage from 15 mg perweek to 45 mg per week in 64 patients was evaluated. The authorsobserved an improvement in disease activity scores (DAS) in somepatients following a switch from oral to intramuscular administration at15 mg per week (average DAS28 reduced from 5.6 to 5.2). Fifty-fourpatients who did not achieve a favorable DAS28 score (DAS28<3.2) alsodemonstrated no difference in disease improvement when compared topatients who were given placebo.

Visser and van der Heijde conducted a review of several studies focusedon the efficacy of varying dosages and modes of administration ofmethotrexate in subjects with rheumatoid arthritis (see Visser, K., andvan der Heijde, D., Annal. Rheum. Diseases, 2008; published online 25Nov. 2008 as doi: 10.1136/ard.2008.092668). The authors concluded thatstarting subjects on methotrexate at 15 mg/week orally, then escalatingthe dose 5 mg/month until a peak concentration of 25-30 mg/week (or thehighest tolerable dose per subject) is reached, followed by a subsequentswitch to subcutaneous administration in the event of an insufficientresponse, seems to be the optimal means of dosing and routing formethotrexate in rheumatoid arthritis.

Varied Bioavailability with Oral Dosing

Several studies have also demonstrated that, when taken orally, thebioavailability of methotrexate is highly variable. There is evidence tosuggest that oral bioavailability of methotrexate declines as the doseis increased. For example, Herman et al. characterized thebioavailability of intravenously and orally administered methotrexate ata dose of 10 mg/m² per week in 41 patients with rheumatoid arthritis(see Herman, R. A., et al., J. Pharm. Sci., 1989; 78: 165-171). Theauthors found that absorption of methotrexate administered orally wasonly about 70%±27% of the total absorption observed followingintravenous administration of the same amount. Additionally, Hamilton etal. compared the bioavailability of intramuscularly administeredmethotrexate versus oral administration at a starting dosage of 7.5 mgper week, with an average maintenance dosage of 17 mg per week, in 21patients with rheumatoid arthritis (see Hamilton, R. A., and Kremer, J.M., Br. J. Rheum., 1997; 36: 86-90). The authors found that the totalabsorption of methotrexate following oral administration fell about13.5% during maintenance dosage relative to the total absorption seen atthe starting dosage.

Kurnik et al. compared the bioavailability of an oral dose ofmethotrexate, ranging from 15 mg to 25 nmg, to the same doseadministered subcutaneously in patients with Crohn's disease (seeKurnik, D., et al., Alimentary Pharm. Ther., 2003; 18: 57-63). Theauthors observed that oral bioavailability varied widely among thepatients given oral doses, with an average bioavailability beingapproximately 73% of the total bioavailability of methotrexate seen inpatients given methotrexate subcutaneously.

Hoekstra et al. evaluated the bioavailability of 25 mg and higher dosesof methotrexate, given orally and subcutaneously, in patients withrheumatoid arthritis (see Hoekstra, M. et al., J. Rheum., 2004; 31:645-8). They reported that oral bioavailability was, on average, only64% of that seen for methotrexate administered subcutaneously at amedian dosage of 30 mg per week. The relative absorption varied from 21%to 96% in the tested patients.

Brooks et al. compared the pharmacokinetics and bioavailability ofmethotrexate administered intramuscularly versus administeredsubcutaneously at doses ranging from 12.5 mg to 25 mg per week (Brooks,P. J. et al., Arthritis and Rheumatism, 1990; 33: 91-94). The authorsfound similar peak serum concentrations and bioavailability for bothroutes, however T_(max) was observed to be faster after subcutaneousadministration in 4 out of 5 patients tested.

Oguey et al. evaluated the effect of food on the bioavailability of oralmethotrexate at a dose of 15 mg in 10 rheumatoid arthritis patients (seeOguey, D., et al., Arthritis and Rheumatism, 1992; 35:611-614). Theyreported that oral bioavailability was unaffected by food, at 67% and63%, respectively, following fasting and fed conditions, however theyalso noted that the inter-patient variability was high, ranging from 28%to 94%.

Hoekstra et al. evaluated the effect of splitting oral doses of 25 mg to35 mg methotrexate into 2 equal portions given 8 hours apart in 10patients with rheumatoid arthritis (see Hoekstra, M., et al., J. Rheum.,2006; 33: 481-485). They showed that bioavailability of a split doseincreased to 90% of that achieved by parenteral administration, ascompared to 76% bioavailability when the same amount was given as asingle oral dose.

Oral Versus Subcutaneous Administration

Recently, Braun et al. reported the results of a 6-month, double-blind,controlled trial comparing the clinical efficacy and safety of orallyadministered methotrexate versus subcutaneously administeredmethotrexate in 375 patients with active rheumatoid arthritis, at astarting dose of 15 mg per week (see Braun, J. et al., Arthritis andRheumatism, 2008; 58: 73-81). After 16 weeks, significantly morepatients who started on subcutaneous methotrexate successfully achievedthe American College of Rheumatology criteria for 20% improvement(ACR20) than those who started on oral methotrexate. Specifically, 85%of patients started on subcutaneous methotrexate achieved an ACR20result versus 77% of those patients started on oral methotrexate.

A trend for greater ACR20 and greater American College of Rheumatologycriteria for 70% improvement (ACR70) scores was also observed after 24weeks. At 24 weeks, the percentage of patients with an ACR20 responsewas significantly higher in a subcutaneously-administered methotrexategroup (78%) than in an orally-administered methotrexate group (70%). Thepercentage of patients achieving an ACR70 response at week 24 was alsohigher in patients receiving subcutaneous methotrexate than in thosereceiving oral methotrexate (41% versus 33%).

At 24 weeks, the number of swollen joints was lower in the group thatreceived subcutaneous methotrexate than in the group that received oralmethotrexate (2 versus 3), as was the number of tender joints (3.5versus 6). The median Health Assessment Questionnaire (HAQ) score, acomprehensive measure of outcome in patients with a wide variety ofrheumatic diseases, was lower in the group administered methotrexatesubcutaneously as compared with the orally administered group at week 24(0.4 versus 0.5). The median Disease Activity Score (DAS28), an indexthat measures the disease activity in patients with rheumatoidarthritis, was also lower in the group administered with methotrexatesubcutaneously than in the orally administered group (3.3 versus 3.7)after 24 weeks.

At 16 weeks, only 52 patients (14% of the total tested) were classifiedas ACR20 non-responders. However, when these patients were switched froma 15 mg oral dose of methotrexate to a 15 mg dose administeredsubcutaneously, 30% of them demonstrated a positive ACR20 response, and23% more of them demonstrated a positive ACR20 response when the dosageof subcutaneously-administered methotrexate was increased from 15 mg to20 mg.

In a subgroup of patients with a time between diagnosis and study entryof ≧1 year who had received prior disease-modifying antirheumaticcompounds or steroids (n=98), the difference in the percentage of ACR20responders between the orally administered (63%) andsubcutaneously-administered (89%) methotrexate groups was even greaterthan in the entire study population. Further, in this group of patients,the time to achieve an ACR20 response was approximately 2 weeks shorterwith subcutaneous administration (4 weeks) of methotrexate than withoral administration (6 weeks).

The authors concluded that superior clinical efficacy was demonstratedwhen methotrexate was administered to subjects subcutaneously ascompared to the same dose of methotrexate given orally. Additionally,subcutaneous administration was not accompanied by a significantlyhigher rate of adverse events.

Oral Versus Intramuscular Administration

Wegrzyn et al. compared the efficacy and tolerability of methotrexateadministered orally versus intramuscularly in a survey of 143 patientswith rheumatoid arthritis (see Wegrzyn, J. et al., Annal. Rheum.Diseas., 2004; 63: 1232-1234). Patients in this study were initiallygiven methotrexate intramuscularly, but were subsequently switched tooral administration following a supply shortage, approximately 3 monthsinto the study. Subsequently, 47 patients were switched back tointramuscular administration of methotrexate and observed for 3 months.

After switching to orally administered methotrexate, 49% to 71% ofpatients reported worsening of symptoms (morning pain and joint pain)and 48% reported experiencing nausea. In the group who were switchedback to intramuscularly administered methotrexate, 40% to 70% ofpatients reported improvement in symptoms (morning pain and joint pain).Somewhat fewer patients (40%) reported nausea. Liver transaminasesincreased in nearly 25% of patients after switching to oral methotrexatewith subsequent decreases after switching back to intramuscularmethotrexate.

Hoffmeister reported on 15 years of early experience with methotrexatein 78 rheumatoid arthritis patients. Patients in this study were given10 mg to 15 mg of intramuscular methotrexate once a week (seeHoffmeister, R. T., Amer. J. Med., 1983; 75(6A):69-73). Eighty-twopercent were judged to have moderate or marked improvement followingtreatment. Patients who achieved the expected maximal effect werepermitted to switch to oral methotrexate. Of the 48 patients whoswitched to oral methotrexate, 10 deteriorated following the switch andsubsequently improved after switching back to intramuscularadministration.

Taken in aggregate, the foregoing pharmacokinetic studies collectivelysuggest that parenteral methotrexate is better absorbed, moreefficacious and better tolerated versus the same dose given orally.

In some embodiments, one or more of the hazardous agents disclosedherein can be injected into a tissue of a subject in less than about 5seconds by a powered injector according to the present disclosure to adepth of from about 2 mm to about 10 mm, in some embodiments from about3 mm to about 5 mm, and in some embodiments about 3.5 mm. In someembodiments, the hazardous agents disclosed herein can be injected intoa tissue of a subject by a powered injector at a pressure range of about200 p.s.i. to about 500 p.s.i., in some embodiments at a range of about300 p.s.i., in some embodiments at about 400 p.s.i., and in someembodiments at about 500 p.s.i. In some embodiments, the poweredinjector is needle-assisted; in some embodiments the powered injector isneedle-free; in some embodiments the powered injector is aneedle-assisted jet injector; and in some embodiments the poweredinjector is a needle-free jet injector.

In some embodiments, a jet injector is configured to render thepharmacokinetics of a hazardous agent, for example methotrexate,unaffected or substantially unaffected compared to other methods ofparenteral delivery including, without limitation, traditional,hand-powered, hypodermic-syringe injection. In some embodiments, a jetinjector is configured, such as by selecting the factors that can affectthe pharmacokinetics, to maintain the speed at which the hazardous agentis absorbed into the subject's bloodstream, and to cause the hazardousagent to be absorbed into the subject's bloodstream at the same rate orsubstantially the same rate as with traditional, hand-powered hypodermicsyringe injection, for maintaining the pharmacokinetics and/orbioavailability for the hazardous agent.

In some embodiments, the depth of injection of a hazardous agent can bealtered in order to deliver that hazardous agent to a subject in such away so as to approximate the known and/or desired pharmacokinetics ofthat hazardous agent. In some embodiments, the depth of injection isincreased in order to maintain the known and/or desired pharmacokineticsof a hazardous agent. In some embodiments, the depth of injection isdecreased in order to maintain the known and/or desired pharmacokineticsof a hazardous agent. In some embodiments, the pressure utilized by ajet injector can be altered in order to deliver a hazardous agent fromthe jet injector into a subject in such a way so as to approximate theknown and/or desired pharmacokinetics of that hazardous agent. In someembodiments, the pressure is increased in order to maintain the knownand/or desired pharmacokinetics of a hazardous agent. In someembodiments, the pressure is decreased in order to maintain the knownand/or desired pharmacokinetics of a hazardous agent. The injectioncharacteristics that will serve to maintain the known and/or desiredpharmacokinetics for a hazardous agent will depend, at least in part, onthe nature of the disease to be treated, the individual subject, and thehazardous agent to be injected, and may be determined by standardtechniques known in the art.

In some embodiments, the depth of injection is altered in order todeliver a dose of methotrexate from a jet injector to a subject suchthat the pharmacokinetics of methotrexate are the same, or substantiallythe same, as the pharmacokinetics of methotrexate administered via othermethods of parenteral delivery including, for example, traditional,hand-powered, hypodermic-syringes. In some embodiments, the pressure ofinjection is altered in order to deliver a dose of methotrexate from ajet injector to a subject such that the pharmacokinetics of methotrexateare the same, or substantially the same, as the pharmacokinetics ofmethotrexate administered via other methods of parenteral deliveryincluding, without limitation, traditional, hand-powered,hypodermic-syringes. In some embodiments, the depth of injection and thepressure of injection are altered in order to deliver a dose ofmethotrexate from a jet injector to a subject such that thepharmacokinetics of methotrexate are the same, or substantially thesame, as the pharmacokinetics of methotrexate administered via othermethods of parenteral delivery including, without limitation,traditional, hand-powered, hypodermic-syringes.

Therapeutic Uses

Hazardous agents of the present disclosure can be administered to apatient, which in some embodiments is a human, suffering from anydisease or disorder for which the disclosed hazardous agents are known,believed to be, or hereafter determined to be therapeutically effectiveincluding, without limitation, cancer, rheumatoid arthritis, juvenilerheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus,steroid-resistant polymyositis or dermatomyositis, Wegener'sgranulomatosis, polyarteritis nodosa, and vasculitis. In certainembodiments, hazardous agents of the present disclosure may be used totreat rheumatoid arthritis.

The suitability of hazardous agents provided by the present disclosurein treating the above-listed diseases may be determined by methodsdescribed in the art.

Dosing

The amount of a hazardous agent that will be effective in the treatmentof a particular disease disclosed herein will depend, at least in part,on the nature of the disease, and may be determined by standardtechniques known in the art. In addition, in vitro or in vivo assays maybe employed to help identify optimal dosing ranges. Dosing regimens anddosing intervals may also be determined by methods known to thoseskilled in the art. The amount of a hazardous agent administered maydepend on, among other factors, the subject being treated, the weight ofthe subject, the severity of the disease, the route of administration,and the judgment of the prescribing physician.

For systemic administration, a therapeutically effective dose of ahazardous agent may be estimated initially from in vitro assays. Initialdoses may also be estimated from in vivo data, e.g., animal models,using techniques that are known in the art. Such information may be usedto more accurately determine useful doses in humans. One having ordinaryskill in the art may optimize administration to humans based on animaldata.

A dose of a hazardous agent, such as that typically available in apre-filled, single shot, preset-dosage injector, for example, can beselected to provide an equivalent molar quantity or mass equivalent doseof a specific hazardous agent. A dose can comprise multiple dosageforms. For example, therapeutically effective doses of methotrexate inpatients can range from about 7.5 mg to about 150 mg per milliliter ofinjection. In certain embodiments, a therapeutically effective dose cancomprise a concentration of methotrexate ranging from about mg to about75 mg per milliliter, in certain embodiments, from about 15 mg to about50 mg per milliliter, and in certain embodiments, from about 15 mg toabout 25 mg per milliliter. In some embodiments, a therapeuticallyeffective dose of methotrexate is selected from about 5 mg/ml, about 10mg/ml, about 15 mg/ml, about 20 mg/ml, about 25 mg/ml, about 30 mg/ml,about 35 mg/ml, about 36 mg/ml, about 37 mg/ml, about 38 mg/ml, about 39mg/ml, about 40 mg/ml, about 41 mg/ml, about 42 mg/ml, about 43 mg/ml,about 44 mg/ml, about 45 mg/ml, about 46 mg/ml, about 47 mg/ml, about 48mg/ml, about 49 mg/ml, about 50 mg/ml, about 51 mg/ml, about 52 mg/ml,about 53 mg/ml, about 54 mg/ml, about 55 mg/ml, about 56 mg/ml, about 57mg/ml, about 58 mg/ml, about 59 mg/ml, about 60 mg/ml, about 61 mg/ml,about 62 mg/ml, about 63 mg/ml, about 64 mg/ml, about 65 mg/ml, about 70mg/ml, about 75 mg/ml, about 80 mg/ml, about 85 mg/ml, about 90 mg/ml,about 95 mg/ml, about 100 mg/ml, about 105 mg/ml, about 110 mg/ml, about115 mg/ml, about 120 mg/ml, about 125 mg/ml, about 130 mg/ml, about 135mg/ml, about 140 mg/ml, about 145 mg/ml, and about 150 mg/ml. The doseof a hazardous agent and appropriate dosing intervals can be selected tomaintain a sustained therapeutically effective concentration of ahazardous agent in the blood of a patient, and in certain embodiments,without exceeding a minimum adverse concentration.

In some embodiments, hazardous agents, inclusive of compounds of formula(I), can be administered via an injector in the management of severe,active rheumatoid arthritis in selected adults and activepolyarticular-course juvenile rheumatoid arthritis in children who haveinsufficient response or cannot tolerate first line therapy, such asnonsteroidal anti-inflammatory compounds (NSAIDs). In some embodiments,dosage of hazardous agents in adult rheumatoid arthritis can be 7.5 mggiven as a single dose or three divided doses of 2.5 mg at 12-hourintervals. In adult rheumatoid arthritis, dosage can be adjustedgradually to achieve optimal response. Hazardous agents, however, can beused at doses up to 25 mg per by the injectable routes disclosed herein.

In certain embodiments, hazardous agents provided by the presentdisclosure may be administered via injectors of the present disclosureonce per day, twice per day, and in certain embodiments at intervals ofmore than once per day. Dosing may be provided alone or in combinationwith other hazardous agents and may continue as long as required foreffective treatment of the disease. Dosing includes administering one ormore of the hazardous agents disclosed herein to a subject, in a fed orfasted state.

A dose may be administered in a single injection or in multipleinjections. When multiple injections are used the amount of a hazardousagent(s) contained within each of the multiple injections may be thesame or different.

In certain embodiments, an administered dose is less than a toxic dose.Toxicity of the hazardous agents described herein is well known in theart and can also be determined by standard pharmaceutical procedures incell cultures or experimental animals, e.g., by determining the LD₅₀(the dose lethal to 50% of the population) or the LD₁₀₀ (the dose lethalto 100% of the population). The dose ratio between toxic and therapeuticeffect is the therapeutic index. In certain embodiments, a hazardousagent may exhibit a high therapeutic index. The data obtained from theart and from these cell culture assays and animal studies may be used informulating a dosage range that is not toxic for use in humans. A doseof a hazardous agent may be within a range of circulating concentrationsin, for example, the blood, plasma, or central nervous system, that istherapeutically effective and that exhibits little or no toxicity.

During treatment a dose and dosing schedule may provide sufficient orsteady state systemic concentration of one or more hazardous agents totreat a disease. In certain embodiments, an escalating dose may beadministered.

It is believed that the hazardous agents of the present disclosure, whenadministered via a powered injector of the present disclosure, willenhance patient compliance by allowing for non-clinical administrationof the hazardous agents via self-administration, as compared torequiring the patient to obtain injections from a medical professional,and as compared to oral dosage forms which may require administration upto several times per week, a regimen that is inconvenient for patientsand difficult for patients to remember. Compliance may be furtherenhanced by the speed at which the powered injectors of the presentdisclosure deliver the hazardous agent(s) into an injection site which,is less than about 5 seconds. Additionally, it is believed that poweredinjectors of the present disclosure are capable of delivering ahazardous agent more precisely, in a controlled manner of delivery,thereby reducing the exposure of the hazardous agents outside of theinjection site and, in some embodiments, eliminating that exposurecompletely. In some embodiments, the injector is pre-filled with one ormore hazardous agents so that the user is not required to draw up thehazardous agent, as they would otherwise be required to do when using ahand-driven, or traditional, syringe. This facilitates operation andaccurate dosing in the administration of hazardous agents, especiallyfor those patients who have a disease or disorder that makes itdifficult for them to draw up medicine and self-inject. It is thereforebelieved that administration of the hazardous agents of the presentdisclosure via powered injectors of the present disclosure will providea safer means of delivery and will significantly reduce the risk ofexposure to the hazardous agents to non-users of the powered injectorsand reduce the risk of unnecessary toxicity to the patient utilizing thepowered injectors.

Administration of hazardous agents as disclosed herein presents a newoption for patients who could benefit from converting from oral dosageforms of a hazardous agent to injection dosage forms of such hazardousagents, but for whom their physicians believe that the current productoptions are not practical for self-injection. The foregoing includes,without limitation, compounds of formula (I). It is also believed thatadministration of hazardous agents via powered injectors of the presentdisclosure will increase simplicity and ease-of-use for patients who mayhave some degree of physical impairment as may be the case in, forexample, rheumatoid arthritis. Additionally, it is believed thatadministration of hazardous agents via injectors of the presentdisclosure will decrease the overall health care costs for subjects byreducing the total number of visits to a health care provider to receiveinjections.

In some embodiments, hazardous agents can be self administered by asubject in less than about 5 seconds via a needle-assisted poweredinjector of the present disclosure. It is believed that the use of apowered injector will make self-administration by subjects easier,increase the consistency of delivery of the hazardous agents by thesubject, reduce the risk of toxicity associated with the hazardousagents, and will therefore enable greater use of hazardous agents totreat maladies such as, for example, rheumatoid arthritis. Further, itis expected that such an injector will extend the clinical utility ofhazardous agents for patients by increasing the consistency ofdelivering a complete dose to the patient, reducing the risk of loss ofthe hazardous agents outside of the injection site, and reducing thetoxicity risk associated with injecting hazardous agents, therebyincreasing overall patient compliance and prolonging the therapeuticdosing potential of hazardous agents prior to switching to biologics,which is the normal clinical practice.

Injectors

Typical hypodermic syringes utilize the force of one or more of a user'sfingers pushing to deliver an injection. In some embodiments, poweredinjectors of the present disclosure are configured to help a subjectrepeatably and accurately administer one or more hazardous agents to apreset depth at each injection in less than about 5 seconds without theneed to utilize such pushing force.

Known autoinjector embodiments of powered injectors use an energy sourcethat produces moderate to low pressure in the medicament chamber so thata medicament contained in the medicament chamber is fired at a slowspeed, similar to the pressure and speed from a finger-driven syringe.In contrast, autoinjector embodiments of the powered injectors of thepresent disclosure use an energy source that produces moderate to highpressure in the medicament chamber so that a medicament contained in themedicament chamber is fired at a fast speed and is completely injectedinto a subject in less than about 5 seconds. Other embodiments of thepowered injectors are jet injectors, which can be needle-assisted orneedle-free jet injectors. Jet injector embodiments can be configured tohave an energy source selected to produce a high pressure in themedicament chamber to eject the medicament with sufficient pressure,force, and speed to exit the injector as a fluid jet. As described ingreater detail below, whereas a medicament injected into a subject viaan autoinjector or hypodermic syringe is delivered in a bolus near theneedle tip, the medicament delivered from a jet injector is sprayedrapidly into the tissue, typically remotely from the needle tip, andtypically does not deposit the medicament in a bolus local to a needletip. Needle-free jet injectors use sufficient pressure and injectionspeed so that the fluid jet breaks through the outer layer of the skin,depositing the medicament thereunder. Needle-assisted jet injectors canuse lower pressures than needle free-jet injectors because they employ aneedle to break through the outer part of the skin, but have pressuresand speeds that are sufficiently high so that the medicament exits theneedle tip as a fluid jet.

Some embodiments of the injectors disclosed herein are single-shotinjectors, configured to deliver in a single shot the entire volume ofthe agent(s) contained within a chamber of the injector or within acartridge contained within the injector. In other embodiments, theinjectors are configured to inject only a portion of the contents of theinjector or a cartridge within the injector and can use dosage-settingmechanisms to enable the selection of the volume of injection to bedelivered in one shot, or other mechanisms to provide an adjustabledosage. In each of the foregoing embodiments, the injector can bepre-filled, or configured to receive a cartridge that has the dosage ofmedicament. Alternative embodiments are configured to be fillable asknown in the art.

Injectors provided by the present disclosure may be utilized by patientsto self-inject one or more hazardous agents. Various aspects of thepresent disclosure relate to self-injection of one or more hazardousagents by a subject without the aid of a health care provider. Incertain embodiments, the injectors use a needle to inject hazardousagents into a target tissue of a subject, such as autoinjector orneedle-assisted jet injector embodiments, while other embodiments areneedle-free injectors and thus do not require a needle to injecthazardous agents into a target tissue of a subject. In certainembodiments, the injectors may utilize pressure sufficient to deliverone or more hazardous agents completely and quickly. In certainembodiments, the injectors may utilize sufficiently high pressure todeliver one or more hazardous agents completely and quickly in a fluidjet.

In some embodiments, powered injectors provided by the presentdisclosure do not require any priming or preparatory step in order toplace them in condition to deliver an injection, thereby reducing oreliminating exposure of the hazardous agent to the air and/or prematureexpulsion of the hazardous agent from a needle of the injector prior tothe delivery shot. Therefore, the risk of contact with the a hazardousagent contained in the injector, by the subject or by a non-user of theinjectors, is reduced or eliminated.

Referring to FIGS. 1-5, an embodiment of an injector according to thepresent disclosure is presented. The embodiment shown in these figuresis a needle injector, and depending on the spring used and deliveryconduit, including the needle and injection outlet, can be configured asan autoinjector or a needle-assisted jet injector. The depicted injector12 has an outer housing member 14 configured for allowing a user tohandle the injector 12 and that substantially houses most of thecomponents shown in FIG. 2. In some embodiments, outer housing 14 isformed from two mating portions 14 a, 14 b that can be configured toattach to one another by a snap or press fit or by using adhesives,welding or the like. Housing 14 includes a fluid chamber 22 therein thatis configured for storing and dispensing one or more liquid medicaments,such as, for example, one or more hazardous agents. In the embodimentshown in FIG. 2, fluid chamber 22 is formed in a prefilled syringe 18that fits within housing 14, but other types of fluid chambers can beused, including known types of cartridges that can be prefilled,refillable, or the like with the medicament(s). Additionally, fluidchamber 22 can be integrally formed within housing 14.

In the embodiment shown, a safety member 80 is located on the proximalend of outer housing 14 and is removably affixed thereto by a pluralityof tabs that extend through matching openings formed in outer housing 14to form a press-fit between safety member 80 and outer housing 14.Safety member 80 is configured to prevent or reduce the likelihood ofunintended firing of the injection device during, for example, shippingor handling of injector 12. Safety member 80 can be removed by a user ofinjector 12 to allow for unrestricted use of injector 12. Alternativeembodiments of the injectors can be constructed without safety member80.

In a further embodiment, a sleeve 16 is housed within and mounted to thehousing 14 and acts as a syringe support member. In some embodiments,the sleeve 16 is configured to hold and position a prefilled syringe 18,carpule or other container of the type known in the art, such as, forexample, a BD Hypak™ prefilled syringe (Becton, Dickinson and Company).One example of a suitable prefilled syringe for use in the depictedembodiments is one which is available in various sizes and volumes andis sold prefilled with medicament, such as the Becton Dickinson Hypak™.In some embodiments, the glass of the syringe body can be adhered to theneedle. Using a prefilled syringe facilitates handling of the medicamentwhen the injector is assembled, and there is an extensive body ofknowledge of how the medicaments keep and behave in a prefilled syringe.In some embodiments, sleeve 16 is substantially fixed to the housing 12,such as by snaps, an adhesive, a weld, or another known attachment. Theprefilled syringe 18 can have a container portion 20 that defines in itsinterior a fluid chamber 22, which is prefilled with an injectablemedicament such as, for example, one or more hazardous agents. In otherembodiments, the medicament container and chamber are provided by otherstructures, such as a chamber that can be integral with or held in thehousing, needle hub 32, or other injection outlet portion of theinjector, for example. At the distal end of the prefilled syringe 18 isan injection-assisting needle 24. Needle 24 has an injecting tip 26configured as known in the art to penetrate the tissue of a patientwhich, in some embodiments, is the skin. A needle bore extends throughthe needle 24, as known in the art. The bore is in fluid communicationwith the medicament in the fluid chamber 22 and is open at the needletip 26 to inject the medicament.

At a proximal end of the fluid chamber 22, opposite from the needle 24,is a plunger 28 that seals the medicament in the fluid chamber 22. Insome embodiments, a syringe wall comprises a tubular portion which, insome embodiments, is closed at a distal end and open at a proximal end,to define the fluid chamber 22. Plunger 28 is slideably received in thetubular portion. The prefilled syringe 18 is configured such that whenthe plunger 28 is displaced in a distal direction, the volume of thefluid chamber 22 is decreased, forcing the medicament out of the chamber22 and through the bore of needle 24. At the distal end of the fluidchamber 22 is a needle hub portion 32 to which the needle is mounted. Asyringe flange 35 extends radially from the proximal end of the syringewall. In injector embodiments that use cartridges, carpules or othercontainers that define a chamber to contain the medicament, the needlecan be fluidly connected with the chamber in a different manner, such asby connecting directly to the cartridge, carpule, or other container, orby connecting to another portion of the injector, such as a housingthereof, by a separate needle hub.

In the embodiment depicted in FIG. 2, the prefilled syringe 18 has asyringe body 36 wherein the flange 35, syringe wall, and hub portion 32is of unitary construction. In some embodiments, the material comprisingthe syringe body 36 is glass, but other materials such as, for example,plastic or metal, can be used in other embodiments.

To radially position the distal end of the prefilled syringe 18, in someembodiments sleeve 16 has a narrowed bore portion 51 that can beconfigured to abut the outside of the syringe wall. This is especiallybeneficial when the needle is inserted into the patient's skin. Thenarrowed bore portion 51 can be made of a resilient material, such as anelastomer, or it can be made unitarily with the rest of sleeve 16, suchas by a series of radially-aligned, resiliently-flexible fingers.Additionally, the proximal portion of the syringe 18 can be held inplace by a shock-absorbing device 33, which, in some embodiments,locates the proximal side of the syringe body 36 radially, and absorbsshocks from the impact of a sudden firing of the ram 60, such as injet-injector embodiments, which produce elevated pressures in the fluidchamber 22 or container 20.

A trigger mechanism can also be housed within housing 14. In someembodiments, the trigger mechanism includes an inner housing 54 that canbe attached to the outer housing 14, such as by snaps, an adhesive, aweld, or other known attachment. Trigger protrusions 56 extend inwardlyfrom the proximal end of the inner housing 54 and are resiliently biasedoutwardly. Trigger protrusions 56 are received in a recess 58 of ram 60in blocking association therewith to prevent distal movement of the ram60 prior to the firing of the device. The ram 60 is moved toward thedistal end of the injector 10 by an energy source, which in someembodiments is a compression spring 52, although in other embodimentsother suitable energy sources can be used such as elastomer orcompressed-gas springs, or a gas generator. An example of a compressionspring 52 suitable for use with injectors of the present disclosure is acoil spring. Alternative embodiments can also use other suitable triggermechanisms as known in the art.

A latch housing 64 can be provided exterior to the inner housing 54 toretain the trigger protrusions 56 in the blocking association in therecess 58 to hold ram 60 in the proximal position until firing isactuated. Latch 64 is slideable inside outer housing 14 with respect tothe inner housing 54, in some embodiments in an axial direction, and insome embodiments latch 64 surrounds the inner housing 54. In someembodiments latch 64 is free to move relative to outer housing 14 and isonly secured in place, after the removal of safety member 80, by thepressure exerted thereon by trigger protrusions 56. In several aspects,nothing is present that biases latch housing 54 away from the proximalend of outer housing 14, including springs or the like. Alternativeembodiments can use a medicament container that is shuttled forward whenthe device is activated to pierce the skin with the needle, and someembodiments use trigger mechanisms that are activated by a button onanother part of the injector, such as at the proximal end or on a sideof the housing as known in the art.

The housing 14 can have a needle guard 66 that is moveable with respectto the outer housing 14. In the embodiment of the needle guard 66 shownin FIG. 2, the needle guard 66 is in a protecting position, in which theneedle 24 is disposed within the guard 66. A ridge 65 (FIG. 8) abuts aninterior surface of outer housing 14 so as to maintain needle guard 66within housing 14 when needle guard 66 is fully extended into theprotecting position. The needle guard 66 can be retractable, in someembodiments into the outer housing 14, in a proximal direction to aninjecting position, in which the needle tip 26 and an end portion of theneedle 24 are exposed as shown in FIGS. 6B and 6C for insertion into apatient. In some embodiments, the proximal movement of the guard 66 isprevented at the injecting position.

The needle guard 66 can be associated with the latch 64 such that whenthe guard 66 is displaced proximally it slides the latch 64 in aproximal direction to release the trigger protrusions 56 from the recess58. In some embodiments, the latch 64 has a latching portion 68 thatabuts the inner housing 54 in an association to bias and maintain thetrigger protrusions 58 positioned in the blocking association with theram 60 prior to the firing of the injector 12. In some embodiments, whenthe latch 64 is slid proximately by the retracting of the guard 66 tothe injecting position, the latching portion 68 slides beyond theportion of inner housing 54 that it contacts and flexes the triggerprotrusions 56 away from the recess 58 of the ram 60, allowing thetrigger protrusions 56 to move radially outwardly from the recess 58 andtherefore from the blocking association. When this happens, spring 52biases the ram 60 against plunger 28 to fire the injector 12.

In some embodiments, a cap 110 can be affixable on the distal end of theinjector 12 so as to cover needle guard 66 and prevent accidentaldisplacement thereof during shipping or during handling prior toinjection. Cap 110 can affix to the distal end of outer housing 14 bypress-fit, screw fit or the like. In certain embodiments, cap 110 caninclude a pair of projections 112 extending inwardly (FIG. 9), that forma distally-facing ridge 114. In such embodiments, needle guard 66 can beformed with a pair of radially-extending flanges 67 (FIG. 8) that areconfigured to abut the distal ridge 114 of projection 112 to secure cap110 to injector 12. In some embodiments, the upper edge 116 (FIG. 9) ofcap 110 can abut the distal end of outer housing 14 such that distalridges 114 of projection 112 are held against flanges 67. Thisarrangement of the cap 110 prevents compression of the needle guard 66proximally into the housing, as the cap 110 is juxtaposed between theguard 66 and housing, securing needle guard 66 in the protectingposition to help prevent accidental firing of the injection mechanism.

In some embodiments, cap 110 can be removed from injector 12 by twistingcap 110 relative to housing 14 such that projections 112 are moved outof alignment with flanges 67, which allows the cap 110 to be moveddistally away from needle guard 66. To prevent accidental removal of cap110 from injector 12 due to inadvertent twisting of cap 110, in someembodiments the cap 110 engages the housing 14 and/or the needle guard66 to require an initially elevated force, such as requiring the cap 110to snap away from its closed position before completing the rotation toremove the cap 110. For example, upper edge 116 of cap 110 can beinclined, as shown in FIG. 9. The incline can include a curve, as shown,but generally the edge 116 can have one edge 118 that is higher than theother edge 120. In some embodiments, the distal end of outer housing 14can have a profile that matches that of upper edge 118 of cap 110. Thisarrangement requires deflection of cap 110 to allow for twisting thereofand increases the force necessary to cause cap 110 to twist relative toneedle guard 66. In an alternative embodiment, the cap 110 can have athreaded or cammed association with the flanges 67, or can have anotherarrangement therewith so that the cap 110 is removed by rotating.

Cap 110 can be attached to injector 12 during assembly thereof. This canbe done by properly aligning cap 110 and twisting it relative to needleguard 66 while applying a proximally-directed force thereto such thatprojections 112 move behind flanges 67. Alternatively, flanges 67 can bestructured to be deflectable inwardly by disposing them on acorresponding tab 69 formed on needle guard 66. In such an embodiment,cap 110 can be assembled onto needle guard 66 prior to assembly ofspring 72 thereinto, as spring 72 can interfere with the inwarddeflection of flanges 67. Alternatively, cap 110 can be resilientlydeformable to allow cap 110 to be pressed onto needle guard 66 such thatprojections 112 pass over flanges 67.

In some embodiments, needle guard 66 can be resiliently biased distallytowards the protecting position by compression coil spring 72. Also, theneedle guard 66 can have an axial opening 74 to allow the needle 24 passtherethrough, and which may be sized according to the type of injectordesired. In some embodiments, the construction of the injector 12 allowsa user to push the distal end of the injector 12 against the patient'sskin, pushing the needle 24 into the skin at an insertion location,substantially at the same speed as the injector 12 is pushed into theskin. Once the needle 24 is fully inserted to an insertion point at adesired penetration depth, the trigger mechanism fires causing theinjector 12 to inject the medicament into an injection site.

In some embodiments, such as for subcutaneous injection using aneedle-assisted jet injector, the needle guard 66 can be configured toallow insertion of the needle 24 to a penetration depth in the skin thatis up to about 5 mm below the skin surface. In some embodiments, thepenetration depth is less than about 4 mm, and in some embodiments lessthan about 3 mm. In some embodiments, the insertion depth is at leastabout 0.5 mm and in some embodiments at least about 1 mm. In anotherembodiment, the distance by which the needle tip 26 extends past theneedle guard 66 or the distal surface of the needle guard 66 thatcontacts the skin is up to about 5 mm, in some embodiments up to about 4mm, and in some embodiments up to about 3 mm. In some embodiments,extension distance is at least about 0.5 mm, in some embodiments atleast about 1 mm, and in some embodiments at least about 2 mm. In someembodiments, needle tip 26 extends past the needle guard 66 by adistance of at least about 2.5 mm beyond the portion of the needle guard66 that contacts the skin in the injecting position.

In another embodiment, such as for intramuscular injection using aneedle-assisted jet injector, the injector 12 can be configured to allowthe needle 24 to be inserted into the patient to a penetration depth inthe skin, or alternatively beyond the distal surface of the needle guard66, by a distance of up to about 15 mm. In some embodiments, thisdistance can be between about 10 mm and about 14 mm. In someembodiments, penetration depth of the needle tip 26 or distance beyondthe needle guard 66 can be between about 12 mm and about 13.5 mm, and insome embodiments about 12.7 mm. Other exposed needle 24 lengths can beselected for jet injection to different depths below the skin, with anoverall penetration length of between about 0.5 mm and about 20 mm. Inthese embodiments, the needle guard 66 can be configured for retractingfrom a protecting position, in some embodiments covering the entireneedle, to an injecting position, in which the desired length of the tip26 of the needle 24 is exposed.

Safety member 80 can be removably affixed to the distal end of outerhousing 14 and can include a body portion 84 and a pair ofresiliently-flexible legs 82 extending therefrom (FIGS. 4A and 4B). Legs82 are configured to extend into corresponding holes or slots 15 formedin the proximal surface of outer housing 14 and can be shaped to providea pressure fit within slots 15 to retain safety member 80 on housing 14.The legs 82 can be biased outwardly and can further include tabs 86disposed on the outside surfaces thereof to engage the inside of outerhousing 14 at the location of slots 15 to further the retention ofsafety member 80 onto outer housing 14. In some embodiments, legs 82 areshaped to allow a user to remove safety member 80 from outer housing 14,when injection is desired. In some embodiments, however, legs 82 preventsafety member 80 from becoming accidentally or unintentionally dislodgedfrom its attachment to outer housing 14.

Legs 82 abut (FIG. 3) the proximal-most surface of latching portion 64when properly attached to outer housing 14 to hinder or prevent jostlingor other motion of latching portion 64 in the proximal direction, whichwould cause the injection mechanism to fire. In some embodiments, legs82 are configured in relationship to the housing 14 and the triggermechanism of the injector 12 such that the force necessary for latchingportion 64 to move legs 82 out of slots is sufficient to preventlatching portion 64 from being jostled out of position due to vibrationduring shipping or from acute shock during shipping or handling causedby dropping of injector 12. Alternative safety members can be used toprevent inadvertent firing of the injector 12.

In an embodiment in which the injector 12 is configured as aneedle-assisted jet injector, the spring 72 and the prefilled syringe 18can be configured to jet inject a medicament such as a hazardous agent.Thus, the spring 72 applies a force on the plunger 28 that can besufficient to elevate the pressure within the fluid chamber 22 to alevel high enough to eject the medicament from the needle 24 as a fluidjet. In several embodiments, jet injection is an injection of medicamentfrom the needle tip 26 of the injector 12 with sufficient velocity andforce to drive the medicament to locations remote from the needle tip26.

Several jet injector embodiments, whether needle-assisted orneedle-free, have an energy source selected to produce a high pressurein the medicament chamber 22 to eject the medicament therefrom withsufficient force and speed to exit the injector 12 as a fluid jet. It isbelieved that jet injectors deliver medicaments rapidly over a widersurface area under the subject's skin, by essentially “spraying” themedicaments into a subject subcutaneously, thereby rapidly exposing agreater surface area of the subject's target tissue to the medicaments.

When delivered by an autoinjector, a medicament typically leaves theautoinjector and is deposited locally, since it is not shot remotelyfrom an injection outlet, and is thus delivered in a bolus near theneedle tip of the autoinjector. This is because an autoinjector requiresadditional injection time to deliver an injection into resistive media,such as tissue, as opposed to delivery into air. In contrast,embodiments of a powered injector disclosed herein, and in particularembodiments of a disclosed jet injector, display no difference ininjection time when injecting into resistive media versus air. Becausethe medicament delivered by a jet injector is essentially sprayedrapidly into the subject's tissue, remotely from the needle tip, themedicament does not leave the jet injector as a single drop or bolus andis thus not delivered to a subject as a bolus local to a needle tip.Therefore, by using the jet injectors disclosed herein, a medicament canbe dispersed into a subject's tissue more efficiently. Additionally,because jet injectors deliver medicaments via high pressure and speed,the delivered medicaments have a far lower tendency to leak back out ofthe injection site around the needle or injection track. Therefore,leak-back from the depth the medicament is delivered back toward theinjection site, and/or back to the surface of the subject's skin, can besignificantly reduced by use of a jet injector. Therefore, when used todeliver one or more medicaments according to the present disclosure,such as, for example, one or more hazardous agents, jet injectorssignificantly reduce the risk of exposure to the medicaments outside ofthe injection site, thereby reducing the risk of exposure to themedicaments to non-users and to the subject himself, in addition toreliably delivering the entire dose to the desired depth. Preventing orreducing leak-back is beneficial in improving compliance by ensuringthat the medicament remains at the injection site at the desired depth.This not only improves the effectiveness of the delivery, but alsoavoids migration of medicaments from the injection site to othertissues, layers of tissue, and/or outside of the injection site.Preventing or reducing leak-back can also be beneficial to keepingmedicaments such as hazardous agents contained to a single area, therebypreventing inadvertent exposure to the subject and/or to otherindividuals in his vicinity from leak-back to the surface of the skin.Such exposure can include, for example, direct contact with themedicament on the subject's skin or from atomized medicament that mayreach the subject or nearby individuals through the air, or thoughanother medium. Additionally, in many cases, patients who use the slowinjection of a hand-powered hypodermic syringe or autoinjector riskremoving the hand-powered injector from the injection site prematurely,before the shot is completed, leading to exposure of the medicamentoutside the patient's tissue, and in some instances leading toaerosolizing of the harmful medicament. This is often due to the longinjection time required for injections via hand-powered hypodermicsyringes or autoinjectors, which can be on the order of 5, 10 or 15seconds or sometimes longer.

In some embodiments, the injector 12 is configured, and the injectionconducted, to deliver a medicament such as, for example, a hazardousagent, that is harmful to the patient or other individuals, by jetinjection in a manner to prevent or significantly reduce leak-back andthe risk and incidence of undue exposure of the medicament to the air orto the outside surface of the patient's skin.

Table 1 shows the results of a trial comparing medicament leak-back thatreached the surface of the skin of a subject after injection; data forneedle-assisted jet injectors as compared to hand-driven hypodermicsyringes is presented. The total number of injections for each group inthe trial was 126, and all were administered by a trained health careprofessional.

TABLE 1 Medicament leak-back to the surface of the skin of a subjectpost injection. % = percent of the total 126 injections administered.Injection site assessment post- Needle-assisted jet injection injectorSyringe and needle Site completely dry 89 (71%) 76 (60%) Slight wetnesson site 36 (29%) 50 (40%) Measurable wetness, but 1 (0%) 0 (0%) slight(a drop) Considerable wetness at 0 (0%) 0 (0%) injection site

Because jet injectors deliver medicaments rapidly, in some embodimentsin less than about 2 seconds, the amount of time patients must hold theinjector in their tissue is dramatically decreased as compared to aninjection delivered by a typical syringe or autoinjector. It istherefore believed that utilizing jet injectors according to the presentdisclosure will result in increased patient compliance and adherence toinstructions and will therefore result in an increase in correctlyadministered injected doses. Additionally, the speed at which jetinjectors deliver medicaments can further enhance patient compliancewith regular injections as the amount of pain experienced by a patientself injecting a medicament will be minimized and, in many cases, maynot exist.

Referring to the graph shown in FIG. 10, numeral 132 represents thepoint in time when an embodiment of injector 12 is fired, and numeral134 represents the point of completion of injection. In someembodiments, injection is completed when the plunger 28 hits the distalwall of the medicament container 20. Numeral 136 represents the initialand peak pressure during the injection, and numeral 130 represents thefinal pressure during the injection. In some embodiments, the spring 72has a linear spring constant and an injection-assisting needle 24 isused to puncture the skin before commencing the injection. The pressureof injection therefore drops substantially linearly from the start ofthe injection 132 until the injection is completed 134. The finalpressure 130 at the end 134 of the injection is sufficiently elevated sothat even at the end of the firing stroke of ram 60, the medicament isstill jet injected, and a very small amount or none of the medicament isdeposited in a bolus around the needle tip 26.

In some embodiments of needle-assisted jet injectors, the peak pressure136 during the injection is less than about 1,000 p.s.i., in someembodiments less than 950 p.s.i., in some embodiments less than 900p.s.i., in some embodiments less than 850 p.s.i., in some embodimentsless than 800 p.s.i., in some embodiments less than 750 p.s.i., in someembodiments less than 700 p.s.i., in some embodiments less than 650p.s.i., in some embodiments less than 600 p.s.i., in some embodimentsless than 550 p.s.i., in some embodiments less than 500 p.s.i., in someembodiments less than 450 p.s.i., in some embodiments less than 400p.s.i., and in some embodiments less than about 350 p.s.i. In someembodiments, at the end 1080 of the injection, the pressure 130 appliedto the medicament in the fluid chamber 22 can be at least about 80p.s.i., in some embodiments at least about 90 p.s.i., in someembodiments at least about 100 p.s.i., in some embodiments at leastabout 150 p.s.i., in some embodiments at least about 200 p.s.i., in someembodiments at least about 250 p.s.i., in some embodiments at leastabout 300 p.s.i., in some embodiments at least about 350 p.s.i., in someembodiments at least about 400 p.s.i., in some embodiments at leastabout 450 p.s.i., and in some embodiments at least about 500 p.s.i. Insome embodiments, the initial pressure 136 can be about 330 p.s.i., andthe final pressure 130 is about 180 p.s.i. In some embodiments, theinitial pressure 136 is about 300 p.s.i., dropping to around 110 p.s.i.at the end 134 of the injection. Other injection rates are used forother embodiments discussed herein. For example, needle-free jetinjectors can exert an injection pressure in the range of about 4,000p.s.i. or greater. Other embodiments of jet injectors utilize lowerinjection pressures, such as at least about 80 p.s.i. or at least about60 p.s.i. In contrast, known autoinjectors typically use pressures lowerthan 60 p.s.i.

The needles used in some embodiments of both autoinjectors andneedle-assisted jet injectors are between 26 and 28 gage, and in someembodiments are around 27 gage. Other needle gages can also be usedwhere the other components are cooperatively configured to produce thedesired injection including, for example, mini-needles. In someembodiments, the components of the injector 12 can be configured to jetinject one or more medicaments to a subcutaneous injection site.

The amount of medicament contained in and injected from fluid chamber 22can be between about 0.02 mL and about 4 mL, in some embodiments lessthan about 3 mL, and in some embodiments is about 1 mL. Larger volumesmay also be selected depending on the particular medicament(s) utilizedand dosage required. In some embodiments, a pre-filled syringe 18containing the desired amount of medicament is assembled into theremaining parts of a jet injector 12. In some embodiments, thepre-filled syringe 18 contains from about 0.02 mL to about 4.00 mL ofone or more medicaments. In some embodiments, the pre-filled syringe 18contains about 1 mL of one or more medicaments.

In embodiments of needle-assisted jet injectors, injection rates arebelow about 0.75 mL/sec., in some embodiments below about 0.6 mL/sec.,in some embodiments at least about 0.2 mL/sec., in some embodiments atleast about 0.3 mL/sec, and in some embodiments at least about 0.4mL/sec. In some embodiments, the injection rate is selected from belowabout 0.75 ml/sec, below about 0.7 ml/sec, below about 0.65 ml/sec,below about 0.6 ml/sec, below about 0.55 ml/sec, below about 0.5 ml/sec,below about 0.45 ml/sec, below about 0.4 ml/sec, below about 0.35ml/sec, below about 0.3 ml/sec, and below about 0.25 ml/sec. In someembodiments, the injection rate is selected from at least about 0.2ml/sec, at least about 0.25 ml/sec, at least about 0.3 ml/sec, at leastabout 0.35 ml/sec, at least about 0.4 ml/see, at least about 0.45ml/sec, at least about 0.5 ml/sec, at least about 0.55 ml/sec, at leastabout 0.6 ml/sec, at least about 0.65 ml/sec, and at least about 0.7ml/sec. In some embodiments, the injection of the entire amount ofmedicament is completed in less than about 5 seconds, in someembodiments in less than about 4.5 seconds, in some embodiments in lessthan about 4 seconds, in some embodiments in less than about 3.5seconds, in some embodiments in less than about 3 seconds, in someembodiments in less than about 2.5 seconds, in some embodiments in lessthan about 2 seconds, and in some embodiments in less than about 1.5seconds. In some embodiments, the medicament injection takes at leastabout 1 second, in some embodiments at least about 1.5 seconds, in someembodiments at least about 1.75 seconds, in some embodiments at leastabout 2 seconds, in some embodiments at least about 2.5 seconds, in someembodiments at least about 3 seconds, in some embodiments at least about3.5 seconds, in some embodiments at least about 4 seconds, and in someembodiments at least about 4.5 seconds. In some embodiments, injectionof the medicament occurs at about 0.5 mL/sec., completing an injectionof 1 mL in about 1 second. In some embodiments, injection of 0.5 ml ofmedicament occurs in less than about 1 second. In some embodiments,injection of 1.0 ml of medicament occurs in less than about 2 seconds.Other injection rates however, are possible for the alternativeembodiments of the injectors 12 disclosed herein. For example, in someembodiments injector 12 can be configured to deliver a typical flow ratefor needle-free jet injection, which can be about 1.5 mL per second, andin some embodiments injector 12 can be configured to deliver a typicalflow rate for an autoinjector, which can be about 0.5 mL in 0.3 seconds.

Injection rates can be affected by a number of factors such as, forexample, the gauge of the needle used to inject the medicament, theviscosity of the medicament itself, the glide force of the plunger 28 inthe syringe barrel, and the temperature of the medicament to beinjected, as temperature can have a direct effect on viscosity. Invarious embodiments, tissue resistance does not impact the rate ofinjection embodiments of the injectors of the present disclosure arecapable of achieving. In various aspects, these parameters can beselected and optimized in order to deliver a volume of injection in adesired manner. Such selection and optimization can be readily performedby a person having ordinary skill in the art without undueexperimentation.

In some embodiments, a viscous medicament that would otherwise require alonger injection time can still be injected into a subject in the ratesset forth above by varying the gauge of the needle. For example, in someembodiments a 26 gauge needle can be utilized with the needle-assistedinjectors of the present disclosure to inject a viscous material, insome embodiments a 27 gauge needle can be utilized with theneedle-assisted injectors of the present disclosure to inject a viscousmaterial, and in some embodiments a 28 gauge needle can be utilized withthe needle-assisted injectors of the present disclosure to inject aviscous material. In each of the foregoing embodiments, the rates ofinjection are the same as those rates disclosed above. Therefore, byvarying the gauge of the needle according to the viscosity of themedicament to be injected, the rates of injection can be maintained. Insome embodiments, a 72 gauge needle can be utilized with one or moreembodiments of the injectors of the present disclosure to deliver 1.0 mlof an aqueous solution into air in a duration of time from between about1.0 to about 2.0 seconds, in some embodiments between about 1.5 andabout 2.0 seconds, and in some embodiments in about 1.7 seconds. In someembodiments, a 72 gauge needle can be utilized with one or moreembodiments of the injectors of the present disclosure to deliver 1.0 mlof an aqueous solution into tissue in a duration of time from betweenabout 1.0 to about 2.0 seconds, in some embodiments between about 1.3and about 2.0 seconds, in some embodiments in about 1.5 seconds, and insome embodiments in about 1.3 seconds. In some embodiments, a 72 gaugeneedle can be utilized with one or more embodiments of the injectors ofthe present disclosure to deliver 1.0 ml of a viscous solution, having aviscosity equivalent to 10% w/w polyethylene glycol 20,000 in water,into air in a duration of time from between about 1.0 to about 5.0seconds, in some embodiments between about 2.5 and about 5.0 seconds, insome embodiments in about 4.3 seconds, and in some embodiments in about4.0 seconds. In some embodiments, a 72 gauge needle can be utilized withone or more embodiments of the injectors of the present disclosure todeliver 1.0 ml of a viscous solution, having a viscosity equivalent to20% w/w polyethylene glycol 20,000 in water, into air in a duration oftime from between about 10 to about 15 seconds, in some embodimentsbetween about 12 and about 15 seconds, and in some embodiments in about14 seconds.

The cgs physical unit for dynamic viscosity is the poise (P), which ismore commonly expressed in ASTM standards as centipoise (cP). Typically,aqueous solutions at 20° C. have a viscosity of approximately 1 cP Inseveral embodiments, injectors of the present disclosure can beconfigured to produce a flow rate, or a rate of injection, of 0.5ml/second for aqueous solutions having a cP of, or close to, 1.0,through a 27 gauge needle. In several embodiments, injectors of thepresent disclosure can be configured to produce a flow rate, or a rateof injection, into skin of 0.5 ml/second for aqueous solutions having acP of, or close to, 1.0, through a 27 gauge needle.

U.S. Pat. No. 6,391,003, discloses the experimental results of pressuresthat can be successfully applied to a medicament in a glass cartridge,using 26 and 27 gage needles. Table 2 illustrates exemplary injectionswith different peak pressures that can be used with a needle-assistedjet injector, especially when using a glass, prefilled syringe:

TABLE 2 exemplary injections that may be delivered by a needle-assistedjet injector. Pressure and Time (sec.) to Inject 1 cc Pressure 26 Gaugeneedle 27 Gauge needle 150 p.s.i. 2.1 4.2 200 p.s.i. 1.9 3.9 240 p.s.i.1.7 3.3 375 p.s.i. 1.4 3.1

A person having ordinary skill in the art will recognize that higherpressures and flow rates will typically, though not always, be used withshorter needle penetration into a patient's skin, to achieve jetinjections with the appropriate dispersion to achieve the desired depthsubstantially without medicament leak-back. Alternative embodiments canuse higher or lower injection pressures. For instance, needle-freeinjectors may use higher pressures to penetrate the skin without aneedle, and autoinjectors will typically use lower pressures to simulatea hand-powered syringe injection.

In some embodiments of needle-assisted jet injectors, short needles canbe used to inject medicaments to different parts of the skin, in someembodiments subcutaneously, without any leak-back. Using a needle 24that extends about 2.5 mm beyond the distal surface of the needle guard66, a 27 gauge needle 24, and a pressure in the fluid chamber 22 peakingat about 300 p.s.i. and ending at around 100 p.s.i., resulting in a flowrate of about 0.5 mL/sec., 1 mL of medicament can be successfully beinjected without significant leak-back in about 100% of the testedinjections as shown, for example, in Table 1 where only slight ormeasurable, but still slight, wetness at an injection site was observed.Thus, needle-assisted jet injectors of the present disclosure permit jetinjection of one or more medicaments using a very short needle reliably,regardless of the thickness of the patient's skin, age, weight or otherfactors.

In some embodiments, selection of the type of spring as a power source,adjustment of the force delivered by the spring, and/or the manner inwhich the spring is packaged within the assembled injector can lead to asignificant reduction in the amount of time required to deliver acomplete injection into a subject, a significant reduction in the springforce required to deliver the injection, and a longer shelf-life. Forexample, the spring present in many known autoinjectors is configured sothat a typical injection, in the volume range of about 0.8-1.5 ml, iscompletely delivered into a subject in 10-15 seconds. In contrast,embodiments of the injectors of the present disclosure can have theirspring configured so as to deliver a complete injection of about0.8-about 1.0 ml in volume in about 1 to about 5 seconds, in someembodiments in about 2 to about 4 seconds, and in some embodiments inabout 3 seconds. It is believed that this decrease in time will increasepatient compliance when embodiments of the autoinjectors of the presentdisclosure are used, as less time is required to deliver a completeinjection and, thus, the patient will experience less pain.

Additionally, in some embodiments spring material can be selected so asto only allow a decrease in spring force over the stroke length of theinjection as shown, for example, in FIG. 16. Many known autoinjectorsshow a decrease in spring force over the course of a single injection ofless than approximately 20%. In contrast, embodiments of the injectorsof the present disclosure can be configured so that their spring forcedecreases by at least about 25% over the course of a single injection,in some embodiments from about 25% to about 50% over the course of asingle injection, in some embodiments from about 30% to about 50% overthe course of a single injection, and in some embodiments by about 50%over the course of a single injection.

Spring material can also be selected, and/or the spring can be set inthe injector, so as to not have the spring in an overly compressed stateduring packaging and shipment of the spring to an end user or patient.This is advantageous because springs that are overly compressed forexpended periods of time become over-stressed and show a loss of forceover time. For example, many known autoinjectors are packaged such thatthey spend most of their shelf-life with their springs compressed. Whenpackaged in this manner, such known autoinjectors experience a decreasein spring force over time as the autoinjector sits on a shelf awaitinguse. In contrast, embodiments of the injectors of the present disclosurecan have springs that are made of a material that is sufficientlyresilient so as to lose less force over time as it is compressed, and/orcan have a spring configured in a fully assembled injector such that itis not in a fully compressed state until the time of injection. In thismanner, embodiments of the injectors of the present disclosure lose fromabout 0% to about 15% of their spring force over a typical shelf life.In some embodiments, the injectors of the present disclosure lose fromabout 10% to about 12% of their spring force over a three year shelflife.

In some embodiments of single-shot injectors, injector 12 includes adisabling mechanism, such as a locking element, which can be provided asa locking ring 70 associated with the injection mechanism. As shown inFIGS. 6A-6D, locking ring 70 can be disposed between sleeve 16 andneedle guard 66, and can interact with sleeve 16 and needle guard 66such that the locking ring 70 only permits needle guard 66 to moverelative to outer housing 14 through a single injection cycle. Thisincludes movement from the protecting position (FIG. 6A) into theinjecting position (FIGS. 6B, 6C) and then to return to the protectingposition (FIG. 6D) under the force of compression spring 72. When needleguard 16 returns to the protecting position at the end of the injectioncycle, locking ring is positioned relative to sleeve 16 and needle guard66 such that further movement therebetween is restricted, thus disablingthe injector from further making injections and retaining the needle 24safely within the housing 14 of the injector 12.

As shown in FIGS. 6A-6D, movement of needle guard 66 through one lockingcycle causes locking ring 70 to move relative to sleeve 16 from aninjecting position to a locking position. In the injecting position,locking ring 70 is disposed such that the upper arms 71 of locking ring70 engage a portion of the device that is associated with the medicamentchamber 22, such as, for example, proximal notches 92 formed in theouter surface of sleeve 16. The engagement of upper arms 71 withinproximal notches 92 releasably maintains locking ring 70 in theinjecting position. As shown in FIG. 7, locking ring 70 can be generallyannular in shape so as to surround the medicament chamber 22, eitherdirectly or indirectly, such as by surrounding sleeve 16. Locking ring70 further includes a pair of lower arms 73, each having a tab 74 formedon the end thereof. When locking ring 70 is in the injecting position,tabs 74 are received in slot 95 formed in needle guard 66 such thatneedle guard 66 is slideable through a predetermined distance overlocking ring 70. As needle guard 66 is moved into the injecting positionwith respect to outer housing 14, needle guard 66 slides over lockingring 70 such that tabs 74 reach the end of slot 95 and are depressedinwardly, allowing needle guard 66 to continue to move into theinjecting position. When the injecting position is reached, tabs 74align with holes 96 of needle guard 66, allowing lower arms 73 to returnto their natural position, wherein the upper surfaces of tabs 74 engagean edge of the holes 96, thereby coupling locking ring 70 to needleguard 66.

As needle guard 66 returns to the protecting position, needle guard 66pulls distally on locking ring 70, causing upper arms 71 to release fromproximal notches 92. In some embodiments, upper arms 71 and proximalnotches 92 are formed with mating inclined surfaces such that theinclined surfaces of upper arms 71 engage another portion of theinjector 12 that is associated with the medicament chamber 22, such asby extending into proximal notches 92, but are forced outwardly bydistally-directed movement relative thereto. This configuration allowsthe needle guard 66 to cause locking ring 70 to move therewith and outof the injecting position as needle guard 66 moves distally toward theprotecting position over sleeve 16, which remains stationary.

When needle guard 66 reaches the protecting position, upper arms 71 moveover distal notches 93 formed in sleeve 16 such that the upper surfacesof upper arms 71 engage the upper surface 94 of distal notches 93.Further, in such a position, flange 77 of locking ring 70 abuts surface67 of needle guard to block needle guard 66 from distal motion relativeto locking ring 70. This engagement prevents locking ring 70 from movingproximally with respect to sleeve 16. Because locking ring 70 is coupledto needle guard 66 in this configuration, and because sleeve 16 isattached to outer housing 14, needle guard 66 is locked relative toouter housing 14, and is prevented from being moved back into theinjecting position. This prevents needle 24 from being accidentallyexposed after use of injector 12. Alternative embodiments can use othermechanisms to prevent re-use of the injector or portion thereof. Someembodiments do not employ such a mechanism so that the injector can bereused. In some embodiments, after injection of the medicament,subsequent injection can be prevented automatically and exposure to orcontact with remnants of the medicament that may remain on portions ofthe injector after the injection, such as on a needle tip or jetinjection nozzle, can also be prevented or avoided by the constructionof the injector 12.

Referring to FIG. 11, a distal end of an embodiment of a needle-free jetinjector is shown. The depicted injector can use the systems disclosedherein to fire the injection as described above for the needle injectorembodiments, but instead of a needle, a jet nozzle 202 is used to injectthe medicament into the subject. Nozzle 202 defines a jet outlet 204having a diameter selected for causing the medicament 200 to exit thenozzle 202 as a fluid jet that is sufficiently strong to pierce theouter skin layers and to continue to the desired depth of injection.

EXAMPLES

The following examples describe in detail the injection andpharmacokinetics of one or more hazardous agents injected into one ormore subjects using embodiments of the injectors disclosed herein. Itwill be apparent to those skilled in the art that many modifications,both to materials and methods, may be practiced without departing fromthe scope of the disclosure.

Example 1

A pharmacokinetic (PK) analysis was undertaken to describe and comparethe systemic exposure of the hazardous agent methotrexate achieved inmale and female Gottingen minipigs after subcutaneous administration,either with an autoinjector of the present disclosure or with a knownhypodermic needle/syringe combination.

Both methotrexate and a control article were administered.Administration of the test and control articles, blood collection andprocessing for this study were performed at Charles River PreclinicalServices (Spencerville, Ohio) under non-FDA compliant GLP (GoodLaboratory Practice) conditions. The plasma concentration data presentedwere produced a Research Grade Level 3 liquid chromatography tandem massspectroscopy (LC-MS/MS) method.

Methotrexate was administered via subcutaneous injection to minipigs,alternatively to the same set of animals with an autoinjector orneedle/syringe. Injections were performed on Day 1 and Day 8. Table 3illustrates the experimental design of the PK portion of the study.

TABLE 3 Number Dose Dose Dose Injection of Dose Level VolumeConcentration Device animals Sex Day^(a) Material (mg/day) (mL) (mg/mL)Autoinjector 3 Males 1 Methotrexate 12.5 0.5 25 3 Females 8 InjectionUSP Needle/Syringe 3 Males 8 Methotrexate 12.5 0.5 25 3 Females 1Injection USP ^(a)The same 3 animals/sex were used on Day 1 and Day 8

Blood samples (approximately 1 mL) were collected from all animals, intoK₂EDTA-containing tubes, according to the schedule in Table 4. Allsamples were processed to plasma prior to being analyzed forMethotrexate and the 7-OH metabolite concentrations. Plasmaconcentration results for the 7-OH metabolite were not subjected to PKanalysis.

TABLE 4 Number of Animals Pharmacokinetic Time Points (Hours PostDose) - Day 1 and Day 8 Males Females 0^(a) 0.25 0.5 0.75 1 1.5 2 4 6 812 24 3 3 X X X X X X X X X X X X ^(a)Sample collected prior to dosing.X Sample collected.

The PK profile of each animal was characterized by non-compartmentalanalysis of Methotrexate plasma concentration data with targetedsampling time points using validated computer software (WinNonlin,Version 5.2.1, Pharsight Corp., Mountain View, Calif., U.S.A.). A modelwas selected based on the extravascular route of administration and theplasma matrix. Predose concentrations were assumed to be zero for thepurpose of PK parameter estimation.

The area under the Methotrexate plasma concentration vs. time curves(AUC) was calculated using the linear trapezoidal method (linearinterpolation). When practical, the terminal elimination phase of the PKprofiles was identified based on the line of best fit using at least thefinal three observed concentration values. The slope of the terminalelimination phase was calculated using log-linear regression using theunweighted concentration data. PK parameters describing the systemicexposure of the test article in the test system were estimated fromobserved (rather than predicted) plasma concentration values, the dosingregimen, the AUC, and the terminal elimination phase rate constant(K_(el)) for each animal. Parameters relying on the determination ofK_(el) were not reported if the coefficient of determination of the lineof best fit (R_(sq)) was less than 0.800, or the extrapolation of theAUC to infinity represented more than 20% of the total area.

Where appropriate, numerical data obtained during the conduct of thestudy were subjected to calculation of descriptive statistics (mean andstandard deviation) in Microsoft Excel, 2000/2003.

As shown in Tables 5 and 6, Methotrexate was above the lower limit ofquantitation (LLOQ=0.2 ng/mL) in a few samples collected prior to dosingon Day 1 and Day 8: Male No. S5196559 (needle/syringe, Day 8, 0.558ng/mL); Male No. S5196206 (needle/syringe, Day 8, 0.222 ng/mL); andFemale No. S5195684 (autoinjector, Day 8, 3.19 ng/mL). These resultswere attributed to carryover of the instrument, from a previous samplecontaining a high concentration of Methotrexate. Methotrexate wasquantifiable in all post dose samples, with the exception of the 24 hsample from Male Nos. S5196273 and S5196206, after administration withautoinjector (Day 1).

TABLE 5 Concentrations of Methotrexate in Gottingen Minipig PlasmaFollowing Subcutaneous Injection of Methotrexate with Autoinjector orSyringe Dose Level: (12.5 mg/day)-Concentration (ng/mL) Nom- inal MalesInjection Time Animal Animal Animal Device (h) S5196273 S5196559S5196206 Mean = SD Auto- Predose BQL BQL BQL BQL = n a  injector 0.251230 1560 1660 1483 = 225  0.5 828 1070 1120 1006 = 156  0.75 585 762668  672 = 88.6 1 402 664 457 508 = 138 1.5 232 461 228 307 = 133 2 121288 146  185 = 90.1 4 26.7 66.1 25.6 39.5 = 23.1 6 7.67 19.4 7.12 11.4 =6.94 8 4.30 7.83 2.73 4.95 = 2.61 12 0.937 1.80 0.692  1.14 = 0.582 24BQL 0.696 BQL 0.232 = 0.402 Syringe Predose BQL 0.558 0.222 0.260 =0.281 0.25 1260 1920 1390 1523 = 350  0.5 999 1510 1470 1326 = 284  0.75705 1110 1240 1018 = 279  1 539 887 860 762 = 194 1.5 245 637 490 457 =198 2 148 367 243 253 = 110 4 25.0 67.9 36.0 43.0 = 22.3 6 6.09 25.514.1 15.2 = 9.75 8 1.91 5.82 2.54 3.42 = 2.10 12 0.501 1.30 0.764 0.855= 0.407 24 0.269 0.780 0.894 0.648 = 0.333 BQL = Below the quantitationlimit (BQL · 0.200 ng mL) The BQL concentrations were assigned a valueof zero for mean calculation. n a = Not applicable.

TABLE 6 Concentrations of Methotrexate in Gottingen Minipig PlasmaFollowing Subcutaneous Injection of Methotrexate with Autoinjector orSyringe Dose Level: (12.5 mg/day)-Concentration (ng/mL) Nom- Injec- inalFemales tion Time Animal Animal Animal Device (h) S5196028 S5195684S5195757 Mean = SD Auto- Predose BQL 3.19 BQL 1.06 = 1.84 injector 0.251530 2240 1720 1830 = 368  0.5 1380 1640 1300 1440 = 178  0.75 1180 1290863 1111 = 222  1 996 1040 627 878 = 220 1.5 635 885 393 638 = 246 2 410549 217 392 = 167 4 75.1 123 49.8 82.6 = 37.2 6 25.1 29.3 20.4 24.9 =4.45 8 9.79 10.1 8.35  9.41 = 0.934 12 6.20 2.43 1.77 3.47 = 2.39 240.617 0.495 0.569  0.560 = 0.0615 Syringe Predose BQL BQL BQL BQL = n a 0.25 1350 1890 1180 1473 = 371  0.5 1280 1520 1250 1350 = 148  0.75 10101200 891 1034 = 156  1 842 940 726 836 = 107 1.5 667 681 398 582 = 160 2449 434 208 364 = 135 4 66.0 84.3 62.3 70.9 = 11.8 6 20.3 24.6 19.8 21.6= 2.64 8 14.0 10.0 18.7 14.2 = 4.35 12 5.12 3.47 6.03 4.87 = 1.30 240.244 0.905 0.230 0.460 = 0.386 BQL = Below the quantitation limit (BQL· 0.200 ng mL) The BQL concentrations were assigned a value of zero formean calculation. n a = Not applicable.

As shown in Table 7, FIG. 12, FIG. 13 and FIG. 14, maximal plasmaconcentrations of Methotrexate were generally observed at the firstcollection time point (0.25 h) with both devices, indicating rapidabsorption from the injection site. After T_(max), Methotrexateconcentrations declined in an apparently bi-exponential fashion. Whereit could be estimated, the terminal elimination half-life ofMethotrexate ranged from 1.81 to 4.90 hours.

TABLE 7 Pharmacokinetic Parameters of Methotrexate in Gottingen MinipigPlasma Following Subcutaneous Injection of Methotrexate withAutoinjector or Syringe Injection Dose Level Animal Cmax Tmax AUC(0-t)AUC(0-inf) T1 2 Cmax AUC(0-t) Device (mg day) Sex No. (ng mL) (h) (ng ·h mL) (ng · h mL) (h) Dose Dose Autoinjector 12.5 Female S5196028 15300.25 2498 2501 3.91 122 200 S5195684 2240 0.25 3169 3172 3.95 179 254S5195757 1720 0.25 1857 1859 3.26 138 149 Mean ^(a) 1830 0.25 2508 25113.71 146 201 SD 368 656 656 0.387 29.4 52.5 Male S5196273 1230 0.25 11621165 1.95 98.4 93.0 S5196559 1560 0.25 1901 1903 2.00 124.8 152 S51962061660 0.25 1405 1407 1.81 132.8 112 Mean ^(a) 1483 0.25 1489 1491 1.92119 119 SD 225 376 376 0.098 18.0 30.1 Syringe 12.5 Female S5196028 13500.25 2378 2378 2.74 108 190 S5195684 1890 0.25 2669 2675 4.90 151 214S5195757 1250 0.50 1831 1832 2.53 100 147 Mean ^(a) 1497 0.25 2293 22953.39 120 183 SD 344 425 428 1.316 27.5 34.0 Male S5196273 1260 0.25 1324^(b) ^(b) 101 106 S5196559 1920 0.25 2464 2466 1.91 154 197 S51962061470 0.50 2016 ^(b) ^(b) 118 161 Mean ^(a) 1550 0.25 1935 — — 124 155 SD337 574 — — 27.0 45.9 ^(a) Median value reported for Tmax. ^(b) Valuesare not reported because the AUC(0-inf) was extrapolated by more than20% or Rsq was 0.800. — Not calculated.

As shown in Table 7, Table 8, FIG. 14 and FIG. 15, exposures obtainedwith either the autoinjector or needle/syringe were very similar.

TABLE 8 Route of Administration Animal Methotrexate Needle/ Sex ID PKParameters Syringe Autoinjector Day 8 Day 1 Male S5196273 Cmax (ng/mL)1260 1230 AUC(0-t) (hr * ng/mL) 1324 1162 Male S5196559 Cmax (ng/mL)1920 1560 AUC(0-t) (hr * ng/mL) 2464 1901 Male S5196206 Cmax (ng/mL)1470 1660 AUC(0-t) (hr * ng/mL) 2016 1405 Day 1 Day 8 Female S5196028Cmax (ng/mL) 1350 1530 AUC(0-t) (hr * ng/mL) 2378 2498 Female S5195684Cmax (ng/mL) 1890 2240 AUC(0-t) (hr * ng/mL) 2669 3169 Female S5195757Cmax (ng/mL) 1250 1720 AUC(0-t) (hr * ng/mL) 1831 1857

As shown in Table 7, FIG. 13 and FIG. 14, there was no marked differencein exposure between males and females, although a very slight trendtowards greater exposure in females, especially through needle/syringeadministration, was observed.

In summary, the pharmacokinetics of methotrexate in plasma wascharacterized in male and female Gottingen minipigs after subcutaneousadministration of 12.5 mg, either with an autoinjector device orneedle/syringe. Maximal concentrations of Methotrexate were generallyobserved shortly (0.25 h) after dose administration, and declinedthereafter, in an apparent bi-exponential manner. The terminalelimination half-life of Methotrexate ranged from 1.81 to 4.90 hours.Exposure achieved with either the autoinjector or needle/syringe wascomparable. There were no marked sex-related differences in PKparameters.

Example 2

A comparison of an injection between an autoinjector of the presentdisclosure and both the Enbrel® SureClick™ Autoinjector (ImmunexCorporation, Thousand Oaks, Calif., U.S.A.) and the HUMIRA® pen (AbbottLaboratories, Abbott Park, Ill., U.S.A.), two known traditionalautoinjectors, was undertaken to describe and compare both the springforce and the time required to deliver a complete injection of asolution in the range of 0.8-1.0 ml.

A control article was administered for this test. The results for thetwo known autoinjectors was averaged. The results of the comparison areshown in FIG. 16. As shown in FIG. 6, the time required to deliver acomplete injection is 10 seconds for the known autoinjectors, whereasthe time required to deliver a complete injection from the autoinjectorof the present disclosure is only 3 seconds. Therefore, users of theknown autoinjectors must retain those autoinjectors at the site ofinjection for a full 10 seconds in order to receive the full injection.In contrast, a user of the autoinjector of the present disclosure needonly retain the autoinjector at the injection site for 3 seconds.

Additionally, as shown in FIG. 16, the spring force required to delivera full injection decreases by approximately 50% in 3 seconds for theautoinjector of the present disclosure. This is in contrast with adecrease in spring force of less than approximately 20% in seconds seenfor the known autoinjectors.

The term “about,” as used herein, should generally be understood torefer to both the corresponding number and a range of numbers. Moreover,all numerical ranges herein should be understood to include each wholeinteger within the range.

While illustrative embodiments of the disclosure are disclosed herein,it will be appreciated that numerous modifications and other embodimentsmay be devised by those skilled in the art. For example, the featuresfor the various embodiments can be used in other embodiments. Therefore,it will be understood that the appended claims are intended to cover allsuch modifications and embodiments that come within the spirit and scopeof the present disclosure.

What is claimed is:
 1. A hazardous agent injection system, the hazardousagent injection system comprising: methotrexate in an amount of fromabout 0.02 ml to about 4.0 ml and at a concentration of from about 7.5mg/ml to about 150 mg/ml; a needle-assisted jet injector, theneedle-assisted jet injector comprising: a container configured tocontain the methotrexate; an injection outlet member associated with thecontainer, the injection outlet member including an injection-assistingneedle configured to pierce the skin of a patient and deliver a jet ofmethotrexate to the patient subcutaneously; a firing mechanismassociated with the container and configured to expel the methotrexatefrom the container through the outlet member for injecting themethotrexate; an energy source associated with the firing mechanism andconfigured to power the firing mechanism and to jet inject themethotrexate from the injection outlet member as a fluid jet; and atrigger mechanism associated with the firing mechanism and configured toactivate the firing mechanism, wherein the needle-assisted jet injectoris configured to eject the methotrexate from the injection outlet membersuch that one or more of confidence intervals of (a) the maximumconcentration of methotrexate in blood plasma of a patient followingadministration of a dose of the methotrexate to the patient (“C_(max)”)with the hazardous agent injection system, (b) the time to reach themaximum concentration of methotrexate in blood plasma of a patientfollowing administration of a dose of the methotrexate to the patientwith the hazardous agent injection system (“T_(max)”) and (c) area underthe curve of the concentration of methotrexate in blood plasma of apatient following administration of a dose of the methotrexate to thepatient with the hazardous agent injection system of the needle-assistedjet injected methotrexate (“AUC”} falls between about 80% and about 125%of a corresponding measured confidence interval of the same dose ofmethotrexate delivered subcutaneously or intramuscularly by ahand-powered syringe, and wherein the needle-assisted jet injector isconfigured to subcutaneously inject the methotrexate in less than 5seconds.
 2. The hazardous agent injection system of claim 1, wherein thegauge of the injection-assisting needle is selected from 26 gauge and ahigher gauge number.
 3. The hazardous agent injection system of claim 1,wherein the needle-assisted jet injector is configured to inject themethotrexate such that the methotrexate is needle-assisted jet injectedat a flow rate of at least about 0.5 ml/sec.
 4. The hazardous agentinjection system of claim 1, wherein the energy source comprises aspring.
 5. The hazardous agent injection system of claim 1, wherein theenergy source is configured for generating a pressure of at least about80 p.s.i. in the container.
 6. The hazardous agent injection system ofclaim 1, wherein the needle-assisted jet injector further comprises anouter housing member configured for allowing a user to handle theinjector.
 7. The hazardous agent injection system of claim 6, theneedle-assisted jet injector further comprises a safety member locatedat the proximal end of the outer housing.
 8. The hazardous agentinjection system of claim 7, wherein the safety member is removablyaffixed to the proximal end of the outer housing.
 9. The hazardous agentinjection system of claim 8, wherein the safety member is removablyaffixed to the proximal end of the outer housing by a plurality of tabsthat extend through matching openings formed in the outer housing toform a press-fit between the safety member and the outer housing. 10.The hazardous agent injection system of claim 1, wherein the containerand the injection outlet member associated with the container comprise asyringe.
 11. The hazardous agent injection system of claim 10, whereinthe needle-assisted injector further comprises a syringe sleeve, thesyringe sleeve having bore portion configured to abut the outside of thesyringe wall so as to minimize syringe movement resulting from of thefiring mechanism action.
 12. A method of treating a patient having anautoimmune disease, the method comprising administering methotrexate tothe patient using the hazardous agent injection system of claim
 1. 13.The method of claim 12, wherein the autoimmune disease is selected fromthe group consisting of rheumatoid arthritis, juvenile rheumatoidarthritis, psoriatic arthritis, systemic lupus erythematosus,steroid-resistant polymyositis or dermatomyositis, Wegener'sgranulomatosis, polyarteritis nodosa, and vasculitis.